Submissions for variant NM_206933.4(USH2A):c.5858C>G (p.Ala1953Gly)

gnomAD frequency: 0.00081  dbSNP: rs41302239

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000041872	SCV000065568	likely benign	not specified	2019-06-28	criteria provided, single submitter	clinical testing	The p.Ala1953Gly variant in USH2A has been identified in several individuals with hearing loss, retinitis pigmentosa, and Usher syndrome but has been identified in 0.1% (144/128948) of European chromosomes (http://gnomad.broadinstitute.org). This frequency suggests that the variant may not be pathogenic. Consistent with this, three individuals tested by our laboratory had alternate genetic explanations of their disease, including one individual who was homozygous for the p. Ala1953Gly variant but harbored another homozygous pathogenic USH2A variant. ACMG/AMP criteria applied: BS1_Supporting, BP2, BP5.
Eurofins Ntd Llc (ga)	RCV000726918	SCV000704147	uncertain significance	not provided	2017-01-03	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000765069	SCV000896269	uncertain significance	Usher syndrome type 2A; Retinitis pigmentosa 39	2018-10-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000726918	SCV000970669	likely benign	not provided	2020-12-03	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 24944099, 27145477, 26868535, 28981474, 28041643, 20507924, 33576794)
Athena Diagnostics	RCV000726918	SCV001146614	uncertain significance	not provided	2019-07-25	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000726918	SCV001147674	likely benign	not provided	2024-07-01	criteria provided, single submitter	clinical testing	USH2A: BP4
Labcorp Genetics (formerly Invitae), Labcorp	RCV000726918	SCV001216189	uncertain significance	not provided	2022-10-24	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 1953 of the USH2A protein (p.Ala1953Gly). This variant is present in population databases (rs41302239, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with retinitis pigmentosa, retinal dystrophy, and Usher syndrome (PMID: 28041643, 28981474, 29142287). ClinVar contains an entry for this variant (Variation ID: 48546). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001196428	SCV001367036	uncertain significance	Usher syndrome type 2A	2019-11-28	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PM1,PP3.
Genome-Nilou Lab	RCV001196428	SCV001737353	uncertain significance	Usher syndrome type 2A	2021-06-10	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001579152	SCV001806576	uncertain significance	Retinitis pigmentosa 39	2021-07-22	criteria provided, single submitter	clinical testing
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV001196428	SCV001984710	likely benign	Usher syndrome type 2A	2020-02-11	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000041872	SCV002500244	uncertain significance	not specified	2022-03-08	criteria provided, single submitter	clinical testing	Variant summary: USH2A c.5858C>G (p.Ala1953Gly) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00084 in 251114 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in USH2A causing Usher Syndrome (0.00084 vs 0.011), allowing no conclusion about variant significance. c.5858C>G has been reported in the literature as a heterozygous genotype in combination with other heterozygous variants in the USH2A gene without phase clearly specified in probands with Retinitis Pigmentosa (RP), Retinal Dystrophies (RD), Pericentral Scotoma, and a reported diagnosis of Usher syndrome (example, Chebil_2016, Comander_2017, Carss_2017, Eandi_2017, Colombo_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Usher Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Thirteen clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign, n=3; VUS, n=10). Based on the evidence outlined above, the variant was classified as uncertain significance.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000726918	SCV004562893	uncertain significance	not provided	2023-09-11	criteria provided, single submitter	clinical testing
Dept Of Ophthalmology, Nagoya University	RCV000504937	SCV004707979	uncertain significance	Retinal dystrophy	2023-10-01	criteria provided, single submitter	research
Laboratory of Prof. Karen Avraham, Tel Aviv University	RCV001196428	SCV005199926	pathogenic	Usher syndrome type 2A	2024-08-20	criteria provided, single submitter	research	The p.(Ala1953Gly) is a known recessive variant based on PMID: 20507924. It was detected in an hearing impaired individual with a sloping audiogram, normal-to-profound HL.
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000504937	SCV000598816	uncertain significance	Retinal dystrophy	2015-01-01	no assertion criteria provided	research
Natera, Inc.	RCV001196428	SCV001455629	uncertain significance	Usher syndrome type 2A	2019-12-31	no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000726918	SCV001959192	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000726918	SCV001972158	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000726918	SCV002034384	uncertain significance	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004724770	SCV005337316	likely benign	USH2A-related disorder	2024-09-03	no assertion criteria provided	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).