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.2522C>A (p.Ser841Tyr)

CA248655

48487 (ClinVar)

Gene: USH2A
Condition: Usher syndrome
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: 7682e5e6-e0b4-41a9-a776-1e192a9bf66e

HGVS expressions

NM_206933.2:c.2522C>A
NM_206933.2(USH2A):c.2522C>A (p.Ser841Tyr)
NM_007123.5:c.2522C>A
NM_206933.3:c.2522C>A
NM_007123.6:c.2522C>A
NM_206933.4:c.2522C>A
ENST00000307340.7:c.2522C>A
ENST00000366942.3:c.2522C>A
NC_000001.11:g.216246872G>T
CM000663.2:g.216246872G>T
NC_000001.10:g.216420214G>T
CM000663.1:g.216420214G>T
NC_000001.9:g.214486837G>T
NG_009497.1:g.181525C>A
NG_009497.2:g.181577C>A

Benign

Met criteria codes 1
BA1
Not Met criteria codes 22
PVS1 BS2 BS1 BS4 BP4 BP3 BP2 BP7 BP5 PS1 PS2 PS4 PS3 PP3 PP4 PP1 PM2 PM6 PM5 PM4 PM3 PM1

Evidence Links 6

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Hearing Loss VCEP
The p.Ser841Tyr variant in the USH2A gene has been identified in three individuals with Usher syndrome (PMIDs 19683999, 28944237, 28653555); however, in two of those individuals a variant on the second allele was not identified (PMIDs 19683999, 28944237) and in one (PMID 28653555), the variant found on the other alleles (p.Tyr1992Cys) did not have evidence to support pathogenicity and has a high allele frequency in gnomAD (of European (Finnish) chromosomes). The filtering allele frequency of the p.Ser841Tyr variant in the USH2A gene is 1.4% for European (Finnish) chromosomes by gnomAD (1144/128242 with 95% CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BA1).
Met criteria codes
BA1
Variant is present in 388/25122 European (Finnish) alleles (1.4% with 95% CI) , 1144/128242 Euorpean (Non-Finnish) alleles (0.8% with 95% CI), and 9 homozygotes in gnomAD.
Not Met criteria codes
PVS1
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 is present in 388/25122 European (Finnish) alleles (1.4% with 95% CI) , 1144/128242 Euorpean (Non-Finnish) alleles (0.8% with 95% CI), and 9 homozygotes in gnomAD.
BS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP2
183 unrelated Spanish patients with Usher syndrome were included in the study and sequenced for MYO7A, USH1C, CDH23, PCDH15, USH1G, USH2A, GPR98 and USH3A. The p.Ser841Tyr variant was observed in 1 patient on 1 allele with no second allele identified. PubMed:19683999
Proband, female onset at 50 years, with amyotrophic lateral sclerosis (ALS) is compound het. for p.S841Y variant and an USH2A p.P4660L variant that is present in 1/30614 South Asian alleles in gnomAD. This observation is irrelevant given that the p.Pro4660Leu variant is not classified as pathogenic. Phenotype is not relevant in a carrier. PubMed:25773295
German proband, 59 y/o, carrying the p.Ser841Tyr variant on one allele and no variant identified on the second allele. PubMed:28944237
19 year old Italian female, RP onset in second decade and severe bilateral SNHL. Diagnosed with USH2. Patient carries p.Ser841Tyr variant and p.Tyr1992Cys variant in USH2A. p.Tyr1992Cys variant is present in >1% of European (Finnish) alleles. PubMed:28653555
BP7
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
PS1
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
PS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS3
conclude the p.S841Y variant is non-pathogenic. No functional studies performed. PubMed:22004887
Assessed allele frequency of variants and concluded benign. PubMed:25262649
PP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP4
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
PM2
Variant is present in 388/25122 European (Finnish) alleles (1.4% with 95% CI) , 1144/128242 Euorpean (Non-Finnish) alleles (0.8% with 95% CI), and 9 homozygotes in gnomAD.
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM5
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
PM3
183 unrelated Spanish patients with Usher syndrome were included in the study and sequenced for MYO7A, USH1C, CDH23, PCDH15, USH1G, USH2A, GPR98 and USH3A. The p.Ser841Tyr variant was observed in 1 patient on 1 allele with no second allele identified. PubMed:19683999
Proband, female onset at 50 years, with amyotrophic lateral sclerosis (ALS) is compound het. for p.S841Y variant and an USH2A p.P4660L variant that is present in 1/30614 South Asian alleles in gnomAD. This observation is irrelevant given that the p.Pro4660Leu variant is not classified as pathogenic. Phenotype is not relevant in a carrier. PubMed:25773295
German proband, 59 y/o, carrying the p.Ser841Tyr variant on one allele and no variant identified on the second allele. PubMed:28944237
19 year old Italian female, RP onset in second decade and severe bilateral SNHL. Diagnosed with USH2. Patient carries p.Ser841Tyr variant and p.Tyr1992Cys variant in USH2A. p.Tyr1992Cys variant is present in >1% of European (Finnish) alleles. PubMed:28653555
PM1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Approved on: 2020-12-24
Published on: 2020-12-24
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