Submissions for variant NM_206933.4(USH2A):c.4586A>T (p.Lys1529Ile)

gnomAD frequency: 0.00190  dbSNP: rs41303255

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000041846	SCV000065542	benign	not specified	2014-08-11	criteria provided, single submitter	clinical testing	Lys1529Ile in Exon 21A of USH2A: This variant is not expected to have clinical s ignificance because it has been identified in 0.7% (30/4406) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs41303255).
Eurofins Ntd Llc (ga)	RCV000041846	SCV000340165	likely benign	not specified	2016-03-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000270447	SCV000354094	uncertain significance	Retinitis pigmentosa	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000324312	SCV000354095	uncertain significance	Usher syndrome type 2A	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
CeGaT Center for Human Genetics Tuebingen	RCV000513149	SCV000608527	uncertain significance	not provided	2017-05-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000513149	SCV001062438	likely benign	not provided	2024-01-31	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV001073300	SCV001238838	uncertain significance	Retinal dystrophy	2018-10-28	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000513149	SCV001473464	benign	not provided	2021-04-13	criteria provided, single submitter	clinical testing
GeneDx	RCV000513149	SCV001783879	likely benign	not provided	2021-05-18	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 26969326)
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV000324312	SCV001984709	likely benign	Usher syndrome type 2A	2020-01-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000041846	SCV002500111	likely benign	not specified	2022-03-04	criteria provided, single submitter	clinical testing	Variant summary: USH2A c.4586A>T (p.Lys1529Ile) results in a non-conservative amino acid change located in the Laminin G domain (IPR001791) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00046 in 250490 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than estimated for a pathogenic variant in USH2A causing Usher Syndrome (0.00046 vs 0.011), allowing no conclusion about variant significance. c.4586A>T has been reported in the literature as a heterozygous genotype in at-least one individual affected with Usher Syndrome who was compound heterozygous for two different causal variants in the USH2A gene (example, Sloan-Heggen_2016). Additionally, it has been reported as a heterozygous genotype in an individual with early onset severe retinal dystrophy (EOSRD) and no evidence of hearing defect who harbored a homozygous nonsense variant in the TTLL5 gene supporting a possible alternate etiology of disease (example, Smirnov_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. Eight 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 and a majority consensus as benign/likely benign (n=5), (VUS, n=3). Based on the evidence outlined above, the variant was classified as likely benign.
Clinical Genetics, Academic Medical Center	RCV000513149	SCV001920831	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000513149	SCV001972776	uncertain significance	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000324312	SCV002093894	benign	Usher syndrome type 2A	2020-01-17	no assertion criteria provided	clinical testing