The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries.
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- See Evidence submitted by expert panel for details.
Variant: NM_206933.2(USH2A):c.8559-2A>G
- Curation Version - 1.0
- Curation History
- JSON LD for Version 1.0
CA262122
48604 (ClinVar)
Gene: USH2A
Condition: Usher syndrome
Inheritance Mode: Autosomal recessive inheritance
UUID: fe785bf9-af38-456e-83ed-6717335dbde4
Approved on: 2018-10-09
Published on: 2019-07-17
HGVS expressions
NM_206933.2:c.8559-2A>G
NM_206933.2(USH2A):c.8559-2A>G
NC_000001.11:g.215877882T>C
CM000663.2:g.215877882T>C
NC_000001.10:g.216051224T>C
CM000663.1:g.216051224T>C
NC_000001.9:g.214117847T>C
NG_009497.1:g.550515A>G
NM_206933.3:c.8559-2A>G
ENST00000307340.7:c.8559-2A>G
More
Pathogenic
Met criteria codes 5
PM4
PP4
PM3_Very Strong
PP1_Strong
PM2_Supporting
Not Met criteria codes 18
PM5
PM1
PS1
PS4
PS2
PS3
BA1
PM6
PP3
PVS1
BS4
BS1
BS2
BP5
BP7
BP3
BP4
BP2
Evidence Links 7
Expert Panel
Evidence submitted by expert panel
Hearing Loss VCEP
The c.8559-2A>G has been detected in >4 patients with Usher syndrome who were compound heterozygous for the this variant in trans with a truncating variant (PM3_VS; PMID: 25356976, 19737284, 26338283, 19023448). Segregation data was also available for two reported families with Usher syndrome. In one family, the variant was identified in trans with a frameshift variant in two affected siblings, and four unaffected siblings were either heterozygous for a single variant or wild-type for both variants. In the second family, an unaffected sibling was heterozygous for a single variant (PP1_Strong, PMID: 19023448). RT-PCR analysis of cells from a patient carrying the variant revealed that the variant causes skipping of exon 43, resulting in a 41 amino acid deletion of the USH2A protein (PM4, PMID: 20596040) The allele frequency of the c.8559-2A>G variant in the USH2A gene is 0.046% (8/17232) of East Asian chromosomes by the Genome Aggregation Database ( http://gnomad.broadinstitute.org), which is a low enough frequency to award PM2_supporting based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss and Usher syndrome (PM2_Supporting). Several patients reported to harbor this variant displayed clinical features of Usher syndrome (PP4; PMID: 25356976, 19737284, 26338283, 19023448). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PM4, PM3_VS, PP1_S, PP4, PM2_P.
Met criteria codes
PM4
RT-PCR analysis of cells from a patient carrying the variant revealed that the variant causes skipping of exon 43, resulting in a 41 amino acid deletion of the USH2A protein (Nakanishi 2010; PM4).
DECIDED TO USE PM4 OVER PS3 ON OUR VARIANT CURATION CALL
PP4
Several patients reported to harbor this variant have clinical features of Usher syndrome, a condition highly specific for Usher syndrome (PP4).
PM3_Very Strong
This variant has been detected in >4 patients with Usher syndrome who were compound heterozygous for the c.8559-2A>G in trans with a truncating variant (PM3_VS; PMID: 25356976, 19737284, 26338283, 19023448).
Identified the variant in a homozygous state in an individual with sporadic NSHL.
PubMed:24853665
2 Usher affected families:
F4: 2 individuals having a p.R34fs frameshift variant in trans with the splice variant. There were 4 unaffected sibs (2 het for p.R34fs, 2 WT/WT).
F3: Variant was inherited in trans with a p.T3936P variant in USH2A in other family. This individual has an unaffected sib with only the p.T3936P variant and experienced HL onset at age 10 while other individuals had congenital HL.
PubMed:19023448
consanguineous family ARRP04: Identified in a homozygous state in one affected individual. Absent from 30 controls. Cite that this variant is a founder variant in East Asian populations.
PubMed:25133613
This study of 67 Chinese Usher syndrome probands identified 11 probands with the variant. They declare that the variant is a founder mutation that accounts for 265 of all Western Japanese USH patients but was never observed in Europeans. The varaint was observed in 5 individuals who were compound het via missense and 6 individuals with nonsense or frameshift variants.
PubMed:26338283
3 probands identified with Usher syndrome. 1 proband has variant in trans with Asp3515Gly (0.25 point), 1 proband has variant in trans with Thr3571Met (LP per LMM, 1 point), 1 proband has the variant in trans with a p.Trp3150X variant, however phase was not confirmed for this individual (0.5 points).
PubMed:19737284
This paper identified 2 compound heterozygotes with IRD and 1 homozygote.
F7-1 (Proband with RP): Variant in trans with a p.T4337M variant in USH2A.
W176-1 (Proband with Usher syndrome): Homozygous state.
W272-1 (Proband with Usher syndrome: Variant in trans with c.8917_8918delCT frameshift variant.
PubMed:25356976
PP1_Strong
Dai et al. 2008 is the only paper with genotyping data for family members. They have a total of 6 unaffected sibs across 2 families and 3 affected individuals with the variant between the two families. (Figure 1) This would actually be 1 affected segregation and 5 unaffected segregations, LOD = 0.75
The variant has been reported in two probands with Usher syndrome. In one family, the variant was identified in trans with a frameshift variant in two affected siblings, and four unaffected siblings were either heterozygous for a single variant or wild-type for both variants. In the second family, an unaffected sibling was heterozygous for a single variant (PP1_Strong, PMID: 19023448).
2 Usher affected families:
F4: 2 individuals having a p.R34fs frameshift variant in trans with the splice variant. There were 4 unaffected sibs (2 het for p.R34fs, 2 WT/WT).
F3: Variant was inherited in trans with a p.T3936P variant in USH2A in other family. This individual has an unaffected sib with only the p.T3936P variant and experienced HL onset at age 10 while other individuals had congenital HL.
PubMed:19023448
PM2_Supporting
The allele frequency of the c.8559-2A>G variant in the USH2A gene is 0.046% (8/17232) of East Asian chromosomes by the Genome Aggregation Database ( http://gnomad.broadinstitute.org), which is a low enough frequency to award PM2 based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for [autosomal dominant / autosomal recessive] hearing loss (PM2).
Not Met criteria codes
PM5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS3
RT-PCR from RNA extracted from hair roots of Japanese Usher syndrome patients (Nakanishi et al 2010) showed that the varaint inactivated the splice acceptor site causing the skipping of the exon 43. (This is currently not in the HL rule document).
AG: downgraded to PS3_Supporting as it is not a functional assay supported by the HL group for application of PS3
RS: not applied
WE DECIDED TO USE PM4 OVER PS3 ON OUR VARIANT CALL
Isolated RNA from hair roots and conducted RT-PCR and found that the c.8559-2A>G variant disrupted splicing which causes the skipping of exon 43.
PubMed:20596040
BA1
The allele frequency of the c.8559-2A>G variant in the USH2A gene is 0.046% (8/17232) of East Asian chromosomes by the Genome Aggregation Database ( http://gnomad.broadinstitute.org), which is a low enough frequency to award PM2 based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for [autosomal dominant / autosomal recessive] hearing loss (PM2).
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP3
All of the splicing predictors in Alamut including MaxEntScan indicate the loss of the splice site that causes the skipping of exon 43.
RS: I wouldn't apply PP3, because it is a splice-site variant.
PVS1
This variant occurs at the -2 site of exon 43, and though this exon is not included in the short transcript of the USH2A gene, the long transcript is the biologically relevant transcript. This change does not remove a significant portion of the protein so PM4 was applied which is equivalent to PVS1_M
BS4
2 Usher affected families:
F4: 2 individuals having a p.R34fs frameshift variant in trans with the splice variant. There were 4 unaffected sibs (2 het for p.R34fs, 2 WT/WT).
F3: Variant was inherited in trans with a p.T3936P variant in USH2A in other family. This individual has an unaffected sib with only the p.T3936P variant and experienced HL onset at age 10 while other individuals had congenital HL.
PubMed:19023448
BS1
The allele frequency of the c.8559-2A>G variant in the USH2A gene is 0.046% (8/17232) of East Asian chromosomes by the Genome Aggregation Database ( http://gnomad.broadinstitute.org), which is a low enough frequency to award PM2 based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for [autosomal dominant / autosomal recessive] hearing loss (PM2).
BS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP7
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP3
RT-PCR analysis of cells from a patient carrying the variant revealed that the variant causes skipping of exon 43, resulting in a 41 amino acid deletion of the USH2A protein (Nakanishi 2010; PM4).
DECIDED TO USE PM4 OVER PS3 ON OUR VARIANT CURATION CALL
BP4
All of the splicing predictors in Alamut including MaxEntScan indicate the loss of the splice site that causes the skipping of exon 43.
RS: I wouldn't apply PP3, because it is a splice-site variant.
BP2
Identified the variant in a homozygous state in an individual with sporadic NSHL.
PubMed:24853665
2 Usher affected families:
F4: 2 individuals having a p.R34fs frameshift variant in trans with the splice variant. There were 4 unaffected sibs (2 het for p.R34fs, 2 WT/WT).
F3: Variant was inherited in trans with a p.T3936P variant in USH2A in other family. This individual has an unaffected sib with only the p.T3936P variant and experienced HL onset at age 10 while other individuals had congenital HL.
PubMed:19023448
consanguineous family ARRP04: Identified in a homozygous state in one affected individual. Absent from 30 controls. Cite that this variant is a founder variant in East Asian populations.
PubMed:25133613
This study of 67 Chinese Usher syndrome probands identified 11 probands with the variant. They declare that the variant is a founder mutation that accounts for 265 of all Western Japanese USH patients but was never observed in Europeans. The varaint was observed in 5 individuals who were compound het via missense and 6 individuals with nonsense or frameshift variants.
PubMed:26338283
3 probands identified with Usher syndrome. 1 proband has variant in trans with Asp3515Gly (0.25 point), 1 proband has variant in trans with Thr3571Met (LP per LMM, 1 point), 1 proband has the variant in trans with a p.Trp3150X variant, however phase was not confirmed for this individual (0.5 points).
PubMed:19737284
This paper identified 2 compound heterozygotes with IRD and 1 homozygote.
F7-1 (Proband with RP): Variant in trans with a p.T4337M variant in USH2A.
W176-1 (Proband with Usher syndrome): Homozygous state.
W272-1 (Proband with Usher syndrome: Variant in trans with c.8917_8918delCT frameshift variant.
PubMed:25356976
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