Submissions for variant NM_000023.4(SGCA):c.421C>A (p.Arg141Ser)

gnomAD frequency: 0.00056  dbSNP: rs35130237

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000713237	SCV000230831	uncertain significance	not provided	2018-03-08	criteria provided, single submitter	clinical testing
GeneDx	RCV000713237	SCV000565557	uncertain significance	not provided	2021-09-17	criteria provided, single submitter	clinical testing	Observed in a patient in the published literature (Boito et al., 2003) with limb-girdle muscular dystrophy who did not have another pathogenic SGCA variant; however, this patient had only mild reduction in alpha-sarcoglycan and normal beta-, delta-, and gamma-sarcoglycan proteins on immunoblot screning on muscle biopsy and Western blot of muscle protein showed a 40% reduction in alpha-sarcoglycan protein; In silico analysis supports that this missense variant does not alter protein structure/function; However, in silico analysis supports this missense variant has a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 18285821, 12746421, 24742800, 31931849)
Invitae	RCV001086384	SCV000649772	likely benign	Autosomal recessive limb-girdle muscular dystrophy type 2D	2024-01-29	criteria provided, single submitter	clinical testing
Athena Diagnostics Inc	RCV000713237	SCV000843823	uncertain significance	not provided	2023-03-17	criteria provided, single submitter	clinical testing	Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is higher than would generally be expected for pathogenic variants in this gene (http://gnomad.broadinstitute.org). Computational tools disagree on the variant's effect on normal protein function.
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000852723	SCV000995438	likely benign	Cardiomyopathy	2017-12-06	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000713237	SCV001246754	uncertain significance	not provided	2020-01-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001122688	SCV001281434	likely benign	Sarcoglycanopathy	2018-01-24	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001086384	SCV001474179	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2D	2020-01-28	criteria provided, single submitter	clinical testing	The SGCA c.421C>A; p.Arg141Ser variant (rs35130237) is reported in the literature in several individuals affected with limb-girdle muscular dystrophy or a related sarcoglycanopathy, although a second SGCA variant was not detected in affected individuals (Boito 2003, Trabelsi 2008). The p.Arg141Ser variant is found in the Latino population with an allele frequency of 0.11% (33/31084 alleles) in the Genome Aggregation Database, and it is reported in ClinVar (Variation ID: 197618). The arginine at codon 141 is weakly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. However, computational analyses of splicing (Alamut v.2.11) predict that this variant may impact splicing by creating a novel cryptic donor splice site, although RNA analyses would be required to confirm this. Given the lack of clinical and functional data, the significance of the p.Arg141Ser variant is uncertain at this time. References: Boito C et al. Novel sarcoglycan gene mutations in a large cohort of Italian patients. J Med Genet. 2003 May;40(5):e67. Trabelsi M et al. Revised spectrum of mutations in sarcoglycanopathies. Eur J Hum Genet. 2008 Jul;16(7):793-803.
Genome-Nilou Lab	RCV001086384	SCV001806722	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2D	2021-07-22	criteria provided, single submitter	clinical testing
Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital	RCV001086384	SCV001984000	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2D	2019-12-29	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001086384	SCV003827593	likely benign	Autosomal recessive limb-girdle muscular dystrophy type 2D	2023-11-30	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000713237	SCV004224392	uncertain significance	not provided	2023-03-21	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001086384	SCV001465521	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2D	2020-04-03	no assertion criteria provided	clinical testing