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

gnomAD frequency: 0.00019  dbSNP: rs143570936

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000710212	SCV000231457	pathogenic	not provided	2016-01-08	criteria provided, single submitter	clinical testing
Athena Diagnostics Inc	RCV000710212	SCV000255838	pathogenic	not provided	2022-01-14	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population is consistent with pathogenicity. (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)) This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant was shown to reduce protein expression and interfere with membrane localization (PMID: 18535179, 22095924). In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic.
Invitae	RCV000179241	SCV000649780	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2D	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 247 of the SGCA protein (p.Val247Met). This variant is present in population databases (rs143570936, gnomAD 0.02%). This missense change has been observed in individual(s) with limb girdle muscular dystrophy type 2D (PMID: 7663524, 9192266, 18285821, 25135358, 25214167, 26404900, 26453141, 26934379). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 167677). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SGCA protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects SGCA function (PMID: 18535179, 22095924). For these reasons, this variant has been classified as Pathogenic.
Illumina Laboratory Services, 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 Munich, Klinikum Rechts Der Isar, Tu München	RCV000179241	SCV001149923	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2D	2020-01-16	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	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 Genetics, 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 Center for Human Genetics Tuebingen	RCV000710212	SCV001246755	pathogenic	not provided	2022-02-01	criteria provided, single submitter	clinical testing
Clinical Genetics and Genomics, 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].
GeneDx	RCV000710212	SCV001794445	pathogenic	not provided	2022-12-05	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect as V247M results in the degradation of the SGCA protein through the ERAD-LM pathway prior to leaving the endoplasmic reticulum (Bianchini et al., 2014); This variant is associated with the following publications: (PMID: 18285821, 26934379, 7663524, 34598035, 22095924, 26453141, 10942431, 18996010, 17994539, 15298081, 29351619, 30919934, 31517061, 31407473, 34426522, 31589614, 31953240, 25214167, 32528171, 33726816, 33458577, 24565866)
Revvity Omics, Revvity	RCV000179241	SCV002020101	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2D	2022-12-21	criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002252007	SCV002523885	pathogenic	See cases	2020-12-03	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS3, PS4, PM2, PM3
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002271422	SCV002556134	pathogenic	Autosomal recessive limb-girdle muscular dystrophy	2022-06-24	criteria provided, single submitter	clinical testing	Variant summary: SGCA c.739G>A (p.Val247Met) results in a 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 0.00011 in 250728 control chromosomes (gnomAD and publication data). This frequency is not significantly higher than expected for a pathogenic variant in SGCA causing Limb-Girdle Muscular Dystrophy, Autosomal Recessive (0.00011 vs 0.002), allowing no conclusion about variant significance. c.739G>A has been reported in the literature in multiple individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive, including homozygotes (Piccolo_1995, Soheili_2012, Magri_2015). These data indicate that the variant is very likely to be associated with disease. Functional studies report experimental evidence evaluating an impact on protein function and this variant results in dramatic reduction of the mutated protein and the absence of the sarcoglycan complex from the cell surface (Gastaldello_2008, Soheili_2012, Bianchini_2014). Fifteen ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Genome-Nilou Lab	RCV000179241	SCV003931695	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2D	2023-02-08	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000179241	SCV004804693	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2D	2024-03-17	criteria provided, single submitter	research
Natera, Inc.	RCV000179241	SCV001455357	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2D	2020-09-16	no assertion criteria provided	clinical testing