Submissions for variant NM_013296.5(GPSM2):c.1492C>T (p.Arg498Ter)

gnomAD frequency: 0.00004  dbSNP: rs370907055

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000604753	SCV000711068	pathogenic	Rare genetic deafness	2016-12-06	criteria provided, single submitter	clinical testing	The p.Arg498X variant in GPSM2 has been reported in the homozygous state in 1 Ir anian individual with hearing loss and in the compound heterozygous state with a nother pathogenic truncating variant in 1 Caucasian individual with Chudley-McCu llough syndrome (CMS) and segregated with disease in two additional family membe rs (Diaz-Horta 2012, Sloan-Heggen 2015). This variant has been identified in 4/6 6726 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac .broadinstitute.org; dbSNP rs370907055). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a rece ssive carrier frequency. This nonsense variant leads to a premature termination codon at position 498, which is predicted to lead to a truncated or absent prote in. In summary, this variant meets criteria to be classified as pathogenic for C hudley-McCullough syndrome in an autosomal recessive manner.
GeneDx	RCV000760407	SCV000890283	pathogenic	not provided	2022-01-25	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27180139, 26445815, 31980526, 22987632, 32445360, 32747562)
Illumina Laboratory Services, Illumina	RCV000778934	SCV000915349	likely pathogenic	GPSM2-Related Disorders	2018-10-10	criteria provided, single submitter	clinical testing	The GPSM2 c.1492C>T (p.Arg498Ter) variant is a stop-gained variant predicted to result in premature termination of the protein. The p.Arg498Ter variant has been reported in two studies in which it has been identified in a total of three individuals with GPSM2-related disorders including in a homozygous state in one individual with a recessive form of profound nonsyndromic hearing loss and in a compound heterozygous state in two siblings with Chudley-McCullough syndrome (CMS) (Diaz-Horta et al. 2012; Sloan-Heggen et al. 2015). Control data are unavailable for this variant, which is reported at a frequency of 0.000111 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the evidence and the potential impact of stop-gained variants, the p.Arg498Ter variant is classified as likely pathogenic for GPSM2-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae	RCV000760407	SCV001580401	pathogenic	not provided	2021-08-24	criteria provided, single submitter	clinical testing
King Laboratory, University of Washington	RCV001727767	SCV001976385	pathogenic	Chudley-McCullough syndrome	2020-08-01	criteria provided, single submitter	research	GPSM2 c.1492C>T leads to a stop at codon 498. It is homozygous in a Palestinian child with severe to profound pre-lingual hearing loss (Abu Rayyan 2020). It is absent from 1300 Palestinian controls and from public databases.
Fulgent Genetics, Fulgent Genetics	RCV001727767	SCV002799092	pathogenic	Chudley-McCullough syndrome	2021-10-09	criteria provided, single submitter	clinical testing