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]

Variant: NM_206933.2(USH2A):c.3902G>T (p.Gly1301Val)

CA143472

48509 (ClinVar)

Gene: USH2A
Condition: Usher syndrome
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: 705d0fbc-b15a-4fc0-9f5e-c1ead022e87e
Approved on: 2024-03-20
Published on: 2024-04-01

HGVS expressions

NM_206933.2:c.3902G>T
NM_206933.2(USH2A):c.3902G>T (p.Gly1301Val)
NC_000001.11:g.216198494C>A
CM000663.2:g.216198494C>A
NC_000001.10:g.216371836C>A
CM000663.1:g.216371836C>A
NC_000001.9:g.214438459C>A
NG_009497.1:g.229903G>T
NG_009497.2:g.229955G>T
ENST00000307340.8:c.3902G>T
ENST00000674083.1:c.3902G>T
ENST00000307340.7:c.3902G>T
ENST00000366942.3:c.3902G>T
NM_007123.5:c.3902G>T
NM_206933.3:c.3902G>T
NM_007123.6:c.3902G>T
NM_206933.4:c.3902G>T
More

Benign

Met criteria codes 1
BA1
Not Met criteria codes 10
BP4 BP1 PS4 PS1 PP3 PP2 PM3 PM1 PM5 PM2

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen Hearing Loss Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for CDH23, COCH, GJB2, KCNQ4, MYO6, MYO7A, SLC26A4, TECTA and USH2A Version 2

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Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Hearing Loss VCEP
The c.3902G>T variant in USH2A is a missense variant predicted to cause substitution of glycine by valine at amino acid 1301 (p.Gly1301Val). The highest population filtering allele frequency with a confidence interval of 0.95 in gnomAD v4.0.0 is 0.5% (469/91078) with 4 homozygotes in the South Asian population, which meets the ClinGen Hearing Loss VCEP criteria for BA1 (≥0.5%). The computational predictor REVEL gives a score of 0.218, which is neither above nor below the thresholds predicting a damaging or benign impact on USH2A function. While this variant has been reported in several individuals with clinical features of USH2A-related disorders, there are no case-control studies and several affected individuals had an alternate cause of disease identified (PMID:21569298, 25649381, 26927203, 32531858). In summary, this variant meets the criteria to be classified as benign, based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP (BA1, ClinGen Hearing Loss VCEP specifications version 2, 03.20.2024).
Met criteria codes
BA1
The highest population filtering allele frequency with a confidence interval of 0.95 in gnomAD v4.0.0 is 0.5% (469/91078) with 4 homozygotes in the South Asian population, which meets the ClinGen Hearing Loss VCEP criteria for BA1 (≥0.5%).
Not Met criteria codes
BP4
The REVEL score is 0.218 which is not low enough to meet BP4.
BP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4
Additional patient with retinitis pigmentosa is homozygous for the p.Gly1301Val variant. This is from a document titled "Chapter 2.3 Hearing in patients with USH2A-associated nsRP". PMID is not available to enter into the Curated Literature Evidence section. Partners LMM reported one proband with moderately-severe mid-frequency SNHL, and a sibling with congenital hearing loss. Proband carries the p.Gly1301Val variant in heterozygosity, but the sibling does not carry the variant (SCB000065531.5). Praxis feur Humangenetic Tuebingen reported two probands with retinal phenotypes who carried the variant. Alternate causes of disease were identified (SCV000574821.4). PS4 is not applied because a 2x2 contingency table was made using the 1 South Asian case, out of 457 affected from the paper, versus the 184 of 30778 South Asian controls.
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP3
The REVEL score is 0.218 which is not high enough to meet PP3.
PP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM3
The p.G1301V variant was reported in compound het. with a p.R878H USH2A variant, with retinal degeneration. The p.R878H variant has been reported as benign by the Partners LMM and is present in gnomAD in 470/30616 South Asian alleles in gnomAD.
PM1
HL VCEP has not specified any mutational hotspots in USH2A.
PM5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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