Submissions for variant NM_206933.4(USH2A):c.1966G>A (p.Asp656Asn)

gnomAD frequency: 0.00071  dbSNP: rs146824138

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hearing Loss Variant Curation Expert Panel	RCV001171539	SCV001334324	likely benign	Usher syndrome	2020-05-25	reviewed by expert panel	curation	The allele frequency of the c.1966G>A (p.Asp656Asn) variant in USH2A is 0.095% (16/10466 CI 95%) of Finnish alleles in gnomAD v3., which is a higher frequency than would be expected for an autosomal recessive pathogenic variant based on the thresholds defined by the ClinGen Hearing Loss Expert Panel (BS1_Supporting). The variant has been identified in 3 probands with hearing loss and 2 probands with Usher syndrome (SCV000065500.6; PMID: 16963483); however an alternate cause of hearing loss in other genes was identified in 3 probands (SCV000065500.6), and a second variant in USH2A was not identified in the other two probands (SCV000065500.6; PMID: 16963483). Finally, in the last proband, another likely benign variant was identified with phasing unknown (SCV000065500.6). Altogether, this evidence does not meet the criteria set to apply PM3_Supporting. Additionally, computational prediction analysis using the metapredictor tool REVEL suggests that the variant may not impact the protein (BP4). In summary, the c.1966G>A (p.Asp656Asn) variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BS1_Supporting, BP4.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000041804	SCV000065500	uncertain significance	not specified	2019-05-10	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The p.Asp656Asn variant in USH2A has been reported in 3 individuals with Usher syndrome and 1 individual with hearing loss (Cremers 2007, LMM data). However, the role of this variant in these 3 individuals remains inconclusive for various reasons (2 of the individuals with Usher syndrome [LMM data] had two pathogenic variants in a different gene that explained disease, the study that reported 1 individual with Usher syndrome did not comment on whether or not a second variant was present [Cremers 2007], and the individual with hearing loss [LMM data], did not harbor a pathogenic variant on the remaining copy of USH2A). In addition, the p.Asp656Asn variant has been reported in 1 individual with inherited isolated retinitis pigmentosa along with 2 additional USH2A variants (p.Thr3667Pro and p.Gln3326X; Carss 2017); however, phase was undetermined. This variant has also been identified in 0.1% (140/126536) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org) and is reported in ClinVar (Variation ID: 48481). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, while the clinical significance of this variant is uncertain, these data suggest that it is more likely to be benign. ACMG/AMP Criteria applied: BS1_Supporting.
GeneDx	RCV000658550	SCV000515232	likely benign	not provided	2020-11-04	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 16963483, 29767709, 28041643, 30245029, 32707200)
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000627016	SCV000747719	uncertain significance	Familial aplasia of the vermis; Congenital cerebellar hypoplasia; Motor delay; Delayed speech and language development; Amblyopia; Hypoplasia of the brainstem; Congenital sensorineural hearing impairment; Cerebellar hemisphere hypoplasia	2017-01-01	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000658550	SCV000780326	uncertain significance	not provided	2021-06-01	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV001075196	SCV001240809	uncertain significance	Retinal dystrophy	2018-11-13	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001099033	SCV001255441	uncertain significance	Usher syndrome type 2A	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV000505164	SCV001255442	uncertain significance	Retinitis pigmentosa	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Invitae	RCV000658550	SCV001413919	likely benign	not provided	2024-01-24	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV001099033	SCV002060040	uncertain significance	Usher syndrome type 2A	2021-10-27	criteria provided, single submitter	clinical testing	NM_206933.2(USH2A):c.1966G>A(D656N) is a missense variant classified as a variant of uncertain significance in the context of USH2A-related disorders. D656N has been observed in cases with relevant disease (PMID: 16963483, 28041643, 31429209). Functional assessments of this variant are not available in the literature. D656N has been observed in population frequency databases (gnomAD: NFE 0.11%). In summary, there is insufficient evidence to classify NM_206933.2(USH2A):c.1966G>A(D656N) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening.
Fulgent Genetics, Fulgent Genetics	RCV002483035	SCV002803635	likely benign	Usher syndrome type 2A; Retinitis pigmentosa 39	2021-07-28	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003944956	SCV004764390	likely benign	USH2A-related condition	2021-04-20	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000505164	SCV000598794	uncertain significance	Retinitis pigmentosa	2015-01-01	no assertion criteria provided	research
Natera, Inc.	RCV001099033	SCV001452250	uncertain significance	Usher syndrome type 2A	2020-09-16	no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000658550	SCV001956365	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000658550	SCV001967987	uncertain significance	not provided		no assertion criteria provided	clinical testing