Submissions for variant NM_206933.4(USH2A):c.14753C>T (p.Thr4918Met)

gnomAD frequency: 0.00172  dbSNP: rs56136489

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000154359	SCV000204022	likely benign	not specified	2015-07-30	criteria provided, single submitter	clinical testing	p.Thr4918Met in exon 67 of USH2A: This variant is not expected to have clinical significance because it has been identified in 0.2% (119/66710) of European chro mosomes, including 1 homozygous individual, by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs56136489). Threonine (Thr) at pos ition 4918 is not conserved in mammals or evolutionarily distant species and 1 m ammal (Pacific walrus) carries a methionine (Met) at this position, suggesting t his change may be tolerated. Additional computational prediction tools do not pr ovide strong support for or against an impact to the protein. Although this vari ant has been reported in one individual with Usher syndrome type II, the authors classified it as a variant of uncertain significance and did not clarify whethe r a second USH2A variant was found in the individual (McGee 2010).
Eurofins Ntd Llc (ga)	RCV000724181	SCV000231964	uncertain significance	not provided	2014-10-16	criteria provided, single submitter	clinical testing
GeneDx	RCV000724181	SCV000616915	uncertain significance	not provided	2021-04-02	criteria provided, single submitter	clinical testing	Identified in a patient with Usher syndrome type II in published literature, however no information about a second variant was provided (McGee et al., 2010); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32707200, 24944099, 20507924)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000724181	SCV001115362	likely benign	not provided	2025-01-07	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000724181	SCV001473486	uncertain significance	not provided	2019-09-25	criteria provided, single submitter	clinical testing	The USH2A c.14753C>T; p.Thr4918Met variant (rs56136489) is reported in the literature in an individual affected with Usher syndrome type 2, although it was not demonstrated to be disease-causing and a second variant in this individual was not reported (McGee 2010). This variant is found in the general population with an overall allele frequency of 0.12% (331/282718 alleles, including one homozygote) in the Genome Aggregation Database. The threonine at codon 4918 is moderately conserved and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. However, due to limited information, the clinical significance of the p.Thr4918Met variant is uncertain at this time. References: McGee TL et al. Novel mutations in the long isoform of the USH2A gene in patients with Usher syndrome type II or non-syndromic retinitis pigmentosa. J Med Genet. 2010 Jul;47(7):499-506.
CeGaT Center for Human Genetics Tuebingen	RCV000724181	SCV002821455	likely benign	not provided	2022-12-01	criteria provided, single submitter	clinical testing	USH2A: BP4, BS2
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV004815236	SCV005070423	uncertain significance	Retinal dystrophy	2023-01-01	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001272929	SCV001455380	likely benign	Usher syndrome type 2A	2020-06-04	no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000724181	SCV001952264	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000724181	SCV001975513	uncertain significance	not provided		no assertion criteria provided	clinical testing