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]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computed assertion could be determined for this classification!

Variant: NM_206933.2(USH2A):c.14276G>A (p.Gly4759Glu)

CA180987

177913 (ClinVar)

Gene: USH2A
Condition: Usher syndrome
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: 1310f3c8-c6e5-4dda-9bc7-535ace6a44e0
Approved on: 2025-05-21
Published on: 2025-06-30

HGVS expressions

NM_206933.2:c.14276G>A
NM_206933.2(USH2A):c.14276G>A (p.Gly4759Glu)
NC_000001.11:g.215650659C>T
CM000663.2:g.215650659C>T
NC_000001.10:g.215824001C>T
CM000663.1:g.215824001C>T
NC_000001.9:g.213890624C>T
NG_009497.1:g.777738G>A
NG_009497.2:g.777790G>A
ENST00000307340.8:c.14276G>A
ENST00000674083.1:c.14276G>A
ENST00000307340.7:c.14276G>A
NM_206933.3:c.14276G>A
NM_206933.4:c.14276G>A
More

Likely Benign

Met criteria codes 1
BS1
Not Met criteria codes 24
BA1 PS1 PS3 PS2 PS4 PP3 PP2 PP4 PP1 PVS1 PM4 PM5 PM1 PM3 PM6 PM2 BS2 BS3 BS4 BP3 BP1 BP2 BP5 BP7

Evidence Links 1

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.14276G>A variant in USH2A is a missense variant predicted to cause substitution of glycine by glutamic acid at amino acid 4759 (p.Gly4759Glu). The filtering allele frequency (the lower threshold of the 95% CI of (295/75006) of this variant is 0.35% for African/African American chromosomes by gnomAD v4, which is higher than the ClinGen Hearing Loss VCEP threshold >0.3% for BS1, and therefore meets this criterion (BS1). It has been detected in at least 4 heterozygous individuals with clinical features of hearing loss or retinitis pigmentosa; however, given the allele frequency and lack of a second pathogenic variant in trans, no evidence is met (PS4/PM3 not met; SCV000204243.5, PMID 28041643). In summary, this variant has been classified as likely benign based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: BS1 (ClinGen Hearing Loss VCEP specifications version 2; 5/21/2025).
Met criteria codes
BS1
Variant has been observed in 102/24022 (0.425%) African alleles in gnomAD
Not Met criteria codes
BA1
Variant has been observed in 102/24022 (0.425%) African alleles in gnomAD
PS1
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
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4
LMM: 3 patients with variable onset, severity of HL and syndromic features were het for the p.Gly4759Glu variant in USH2A and did not carry any other USH2A variants. No patients had RP reported. Carss 2017: Patient has 4 USH2A variants, can't count this as a PM3 case but might use this variant as a case-control.
Patient G005232: Patient has RP, African male. Patient has 4 variants in USH2A USH2A p.Gly4759Glu (VUS/LB) USH2A p.Pro4232Gln (VUS) USH2A p.Leu2962Ile (VUS) USH2A p.Gln2951Glu (VUS) PubMed:28041643
PP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP2
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
PVS1
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
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
PM3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM2
Variant has been observed in 102/24022 (0.425%) African alleles in gnomAD
BS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS4
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
BP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP5
Patient has 4 variants in USH2A with RP and the case is considered "partially solved" but none of these variants are considered LP or P so this cannot be used.
Patient G005232: Patient has RP, African male. Patient has 4 variants in USH2A USH2A p.Gly4759Glu (VUS/LB) USH2A p.Pro4232Gln (VUS) USH2A p.Leu2962Ile (VUS) USH2A p.Gln2951Glu (VUS) PubMed:28041643
BP7
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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