Submissions for variant NM_206933.4(USH2A):c.12874A>G (p.Asn4292Asp)

gnomAD frequency: 0.00003  dbSNP: rs397517984

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hearing Loss Variant Curation Expert Panel	RCV001075301	SCV001428433	likely pathogenic	Retinal dystrophy	2024-05-15	reviewed by expert panel	curation	The c.12874A>G variant in USH2A is a missense variant predicted to cause substitution of asparagine by aspartic acid at amino acid 4292 (p.Asn4292Asp). The highest population frequency in gnomAD v4.1.0 is 0.02% (20/86258 alleles) in the South Asian population (PM2_Supporting, BS1, and BA1 are not met). The computational predictor REVEL gives a score of 0.707, which is above the threshold of 0.7, evidence that correlates with impact to USH2A function (PP3). This variant has been identified in at least 6 individuals with apparently isolated retinal dystrophy. One individual was homozygous, one was heterozygous for a second variant of uncertain significance, three had a second pathogenic variant with phase unknown, and one harbored a second pathogenic variant confirmed in trans (2 points, PM3_Strong, PMID: 28041643, 25133751, 37322672, Invitae Internal evidence SCV001403886.5, Blueprint Genetics internal evidence SCV001240918.1). The variant has been reported to segregate with retinal dystrophy in 1 affected family member from 1 family (PP1; PMID: 25133751). Of note, hearing loss was not reported in any of these individuals, indicating that this variant is likely causative for isolated retinal dystrophy and not Usher syndrome. In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive inherited retinal dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PP3, PM3_Strong, PP1. (Hearing loss VCEP specifications version 2; 05.15.2024).
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000041732	SCV000065428	uncertain significance	not specified	2012-01-16	criteria provided, single submitter	clinical testing	The Asn4292Asp variant in USH2A has not been reported in the literature nor prev iously identified by our laboratory. Computational analyses (biochemical amino a cid properties, homology, PolyPhen2, SIFT, AlignGVGD) do not provide strong supp ort for or against pathogenicity.
Blueprint Genetics	RCV001075301	SCV001240918	pathogenic	Retinal dystrophy	2017-11-28	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001231366	SCV001403886	pathogenic	not provided	2024-02-13	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 4292 of the USH2A protein (p.Asn4292Asp). This variant is present in population databases (rs397517984, gnomAD 0.02%). This missense change has been observed in individual(s) with retinitis pigmentosa (PMID: 25133751, 28041643; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 48409). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on USH2A protein function. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001231366	SCV001985357	uncertain significance	not provided	2020-10-08	criteria provided, single submitter	clinical testing	Observed phase unknown with a second USH2A variant in a patient with retinitis pigmentosa in published literature (Carss et al., 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar as a variant of uncertain significance by the ClinGen Hearing Loss Expert Panel (SCV001428433.1; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 28041643, 25133751, 32637036, 32581362)
Myriad Genetics, Inc.	RCV001810411	SCV002060272	uncertain significance	Usher syndrome type 2A	2021-11-16	criteria provided, single submitter	clinical testing	NM_206933.2(USH2A):c.12874A>G(N4292D) is a missense variant classified as a variant of uncertain significance in the context of USH2A-related disorders. N4292D has been observed in cases with relevant disease (PMID: 25133751, 28041643). Functional assessments of this variant are not available in the literature. N4292D has been observed in population frequency databases (gnomAD: SAS 0.02%). In summary, there is insufficient evidence to classify NM_206933.2(USH2A):c.12874A>G(N4292D) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening.
Baylor Genetics	RCV003460549	SCV004208173	likely pathogenic	Retinitis pigmentosa 39	2024-01-23	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005016325	SCV005645513	likely pathogenic	Usher syndrome type 2A; Retinitis pigmentosa 39	2024-06-23	criteria provided, single submitter	clinical testing
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000504620	SCV000598780	likely pathogenic	Retinitis pigmentosa	2015-01-01	no assertion criteria provided	research