Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
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  • See Evidence submitted by expert panel for details.

Variant: NM_206933.2(USH2A):c.8682-9A>G

CA275277

197510 (ClinVar)

Gene: USH2A
Condition: Usher syndrome
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: b0b1e906-0446-4e9d-a092-fdd3fdce63ef

HGVS expressions

NM_206933.2:c.8682-9A>G
NM_206933.2(USH2A):c.8682-9A>G
NC_000001.11:g.215867179T>C
CM000663.2:g.215867179T>C
NC_000001.10:g.216040521T>C
CM000663.1:g.216040521T>C
NC_000001.9:g.214107144T>C
NG_009497.1:g.561218A>G
NM_206933.3:c.8682-9A>G
ENST00000307340.7:c.8682-9A>G

Pathogenic

Met criteria codes 4
PM3_Very Strong PP4 PP3 PM2_Supporting
Not Met criteria codes 17
PS4 PS2 PS3 BP7 BP5 BP2 BP4 BP3 PP1 BA1 PM6 PVS1 PM1 PM4 BS2 BS1 BS4

Evidence Links 5

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Hearing Loss VCEP
The c.8682-9A>G variant in USH2A has been detected in patients with hearing loss in trans with at least 4 pathogenic or suspected-pathogenic variants (PM3_VS; PMID: 27318125, 25425308, 28944237, 23591405). The allele frequency of the c.8682-9A>G variant in the USH2A gene is 0.04% (5/10112) of Ashkenazi Jewish 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 (PM2_P). At least one patient with this variant displayed features of retinitis pigmentosa and hearing loss which is consistent with Usher syndrome (PP4; PMID: 27318125, 25425308, 28944237, 23591405). Computational prediction tools and conservation analysis suggest that the c.8682-9A>G variant may impact the protein (PP3). 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: PM3_VS, PM2_Supporting, PP4, PP3.
Met criteria codes
PM3_Very Strong
See Neuhaus 2017 JM ANDREA: I think that we can score the truncating variants as at least Likely pathogenic, therefore for Neuhaus and Glockle, I scored a total of 3 points for PM3. Adding all of my points I got 4 points for PM3, which is enough to apply PM3_VeryStrong. However, there is no option to do so in the variant curation interface.
1 homozygote with variant for 0.25 points under PM3. The homozygote was displayed in the supplemental table S2. PubMed:27318125
1 homozygote and 2 compound hets with rare VUS with Usher syndrome, total of 0.75 points for PM3. The compound hets harbored Leu1673Pro, and I was not sure if they were sibs, so scored lower points under PM3 versus scoring a segregation under PP1. PubMed:25425308
1 cpd het with Glu767SerfsX21 that is P by ClinVar (multiple submitters, no conflicts2 stars out of maximum of 4 stars). also identified 1 cpd het with Trp4175X also not classified not scored, and 1 additional het identified from same cohort (Germans) PubMed:28944237
1 sporadic cpd het with E4078EfsX20 (same individual in Baux 2007) with type 2 also harbors Val218Glu (neither classified ClinVar) not counted PubMed:23591405
PP4
We decided that Usher syndrome was specific enough to use PP4 - Andrea
PP3
Applied PP3 here since it is not available on the Silent/Intron tab. Splice predictions in Alamut, including SpliceSiteFinder LIke, MaxEntScan, predict stronger splicing at variant, which would add 8 nucleotides
PM2_Supporting
Variant present in 0.04% 5/10112) Ashkenazi Jewish chromosomes, meets PM2_Supporting
Not Met criteria codes
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
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP7
Conflicting information Alamut: New splice acceptor in mutant may be preferred over WT, SpliceSiteFinder-like supports impact (PP3)JM
IVS43, reporting 2 alleles classified as UV2 LOVD interpreted as likely neutral PubMed:27318125
variant ID in this study as novel (IVS43). Variant unclassified (Scandinavian) individual with type 2. Variant presumed to not conflict with splicing process. PubMed:18273898
BP5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP2
1 homozygote with variant for 0.25 points under PM3. The homozygote was displayed in the supplemental table S2. PubMed:27318125
1 homozygote and 2 compound hets with rare VUS with Usher syndrome, total of 0.75 points for PM3. The compound hets harbored Leu1673Pro, and I was not sure if they were sibs, so scored lower points under PM3 versus scoring a segregation under PP1. PubMed:25425308
1 cpd het with Glu767SerfsX21 that is P by ClinVar (multiple submitters, no conflicts2 stars out of maximum of 4 stars). also identified 1 cpd het with Trp4175X also not classified not scored, and 1 additional het identified from same cohort (Germans) PubMed:28944237
1 sporadic cpd het with E4078EfsX20 (same individual in Baux 2007) with type 2 also harbors Val218Glu (neither classified ClinVar) not counted PubMed:23591405
BP4
Applied PP3 here since it is not available on the Silent/Intron tab. Splice predictions in Alamut, including SpliceSiteFinder LIke, MaxEntScan, predict stronger splicing at variant, which would add 8 nucleotides
BP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BA1
Variant present in 0.04% 5/10112) Ashkenazi Jewish chromosomes, meets PM2_Supporting
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PVS1
?. The loss of USH2A function is an established disease mechanism in autosomal recessive Usher syndrome. Though not impacting canonical splice site +/-2 new acceptor may be preferred over WT JM
PM1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS1
Variant present in 0.04% 5/10112) Ashkenazi Jewish chromosomes, meets PM2_Supporting
BS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Approved on: 2018-09-24
Published on: 2019-07-17
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