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

gnomAD frequency: 0.00003  dbSNP: rs397517984

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hearing Loss Variant Curation Expert Panel	RCV001252674	SCV001428433	uncertain significance	Usher syndrome	2020-07-28	reviewed by expert panel	curation	The c.12874A>G (p.Asn4292Asp) variant in USH2A was present in 0.01% (7/30616) of South Asian alleles in gnomAD v2.1.1 and was absent from gnomAD v3 (PM2_Supporting). It has been identified in the homozygous state in 1 proband with retinitis pigmentosa and segregated with disease in 2 additional family members (PM3_Supporting; PP1_Moderate; PMID: 25133751). The p.Asn4292Asp variant has also been identified in a proband with Hearing loss and Retinitis pigmentosa who carried a variant of uncertain significance in OTOF (SCV000065428.6). Finally, a patient with Retinitis pigmentosa carried a second variant of unknown significance in USH2A with phase unknown (PMID: 28041643, ClinVar ID: 438010). The REVEL computational prediction analysis tool produced a score of 0.707, which is above the threshold necessary to apply PP3. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel : PM2_Supporting, PM3_Supporting, PP1_Moderate, PP3.
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
Invitae	RCV001231366	SCV001403886	pathogenic	not provided	2023-03-21	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 48409). 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. This variant is present in population databases (rs397517984, gnomAD 0.02%). 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).
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	2023-10-16	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