ClinVar Miner

Submissions for variant NM_000023.4(SGCA):c.739G>A (p.Val247Met) (rs143570936)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 12
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000710212 SCV000231457 pathogenic not provided 2016-01-08 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000710212 SCV000255838 pathogenic not provided 2017-10-24 criteria provided, single submitter clinical testing
Invitae RCV000179241 SCV000649780 pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2D 2020-10-10 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 247 of the SGCA protein (p.Val247Met). The valine residue is moderately conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs143570936, ExAC 0.02%). This variant has been reported in the homozygous or compound heterozygous state in many individuals affected with limb girdle muscular dystrophy type 2D (PMID: 26453141, 25135358, 7663524, 18285821, 9192266, 26404900, 26934379, 25214167). ClinVar contains an entry for this variant (Variation ID: 167677). Experimental studies have shown that this variant leads to reduced expression and cellular mislocalization of the alpha-sarcoglycan protein (PMID: 22095924, 18535179). For these reasons, this variant has been classified as Pathogenic.
Illumina Clinical Services Laboratory,Illumina RCV000779226 SCV000915771 pathogenic Sarcoglycanopathy 2018-09-07 criteria provided, single submitter clinical testing Across a selection of available literature, the SGCA c.739G>A (p.Val247Met) variant has been identified in a homozygous state in two probands, in a compound heterozygous state in at least 11 probands, and in a heterozygous state in three probands in whom a second variant was not identified (Piccolo et al. 1995; Eymard et al. 1997; Crosbie et al. 2000; Moreira et al. 2003; Klinge et al. 2008; Guglieri et al. 2008; Trabelsi et al. 2008; Mendell et al. 2010). Control data are not available for this variant, which is reported at a frequency of 0.000238 in the European (non-Finnish) population of the Genome Aggregation Database. Functional studies in HEK293 cells demonstrated that the p.Val247Met variant increases ubiquitination and degradation of alpha-sarcoglycan via the E3 ligase HRD1, and inhibition of this pathway in myotubes derived from a limb-girdle muscular dystrophy type 2D patient carrying the p.Val247Met variant rescued alpha-sarcoglycan expression at the cell membrane (Bianchini et al. 2014). Based on the collective evidence, the p.Val247Met variant is classified as pathogenic for alpha-sarcoglycanopathy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Belal Azab Laboratory,The University of Jordan RCV000179241 SCV000930014 pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2D 2019-07-01 criteria provided, single submitter research
Institute of Human Genetics, Klinikum rechts der Isar RCV000179241 SCV001149923 pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2D 2020-01-16 criteria provided, single submitter clinical testing
Broad Institute Rare Disease Group, Broad Institute RCV000179241 SCV001164529 pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2D 2018-12-03 criteria provided, single submitter research The heterozygous p.Val247Met variant in SGCA was identified by our study in two unrelated individuals in the compound heterozygous state, with another pathogenic variant, in individuals with limb-girdle muscular dystrophy (LGMD). This variant has been identified in 0.02379% (30/126108) of European (non-Finnish) chromosomes, in 0.005816% (2/34386) of Latino chromosomes, and 0.004167% (1/23998) of African chromosomes in the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs143570936). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. The p.Val247Met variant in SGCA has been reported in many individuals with Limb-Girdle Muscular Dystrophy and segregated with disease in 2 affected relatives from 1 family (PMID: 15298081). the presence of this variant in combination with a reported pathogenic variant and in an individual with Limb-Girdle Musclar Dystrophy increases the likelihood that the p.Val247Met variant is pathogenic. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. Functional assays provide some evidence that the p.Val247Met variant may impact protein function by reducing protein localization to the membrane and expression in the muscle tissue (PMID: 15298081, 22095924). However, these types of assays may not accurately represent biological function. This variant has also been reported pathogenic and likely pathogenic in ClinVar (Variation ID: 167677). In summary, the p.Val247Met variant is pathogenic based off of our findings, multiple reports in ClinVar, and the literature. ACMG/AMP Criteria applied: PS3, PM3_Strong, PM2, PP1 (Richards 2015).
Myriad Women's Health, Inc. RCV000179241 SCV001194125 likely pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2D 2020-01-06 criteria provided, single submitter clinical testing NM_000023.2(SGCA):c.739G>A(V247M) is classified as likely pathogenic in the context of alpha-sarcoglycanopathy. Sources cited for classification include the following: PMID 22095924, 24565866, 18535179, 18996010, 7663524, 17994539 and 25135358. Classification of NM_000023.2(SGCA):c.739G>A(V247M) is based on the following criteria: This variant has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000710212 SCV001246755 pathogenic not provided 2018-04-01 criteria provided, single submitter clinical testing
Clinical Genetics Karolinska University Hospital,Karolinska University Hospital RCV000710212 SCV001450014 likely pathogenic not provided 2018-12-07 criteria provided, single submitter clinical testing
Baylor Genetics RCV000179241 SCV001522757 pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2D 2020-04-12 criteria provided, single submitter clinical testing This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Natera, Inc. RCV000179241 SCV001455357 pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2D 2020-09-16 no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.