ClinVar Miner

Submissions for variant NM_000023.4(SGCA):c.421C>A (p.Arg141Ser) (rs35130237)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000713237 SCV000230831 uncertain significance not provided 2018-03-08 criteria provided, single submitter clinical testing
GeneDx RCV000713237 SCV000565557 uncertain significance not provided 2018-07-16 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the SGCA gene. The c.421 C>A variant has been reported previously in an individual with limb-girdle muscular dystrophy who did not have another SGCA pathogenic variant; however, this patient had only mild reduction in alpha-sarcoglycan and normal beta-, delta-, and gamma-sarcoglycan proteins on immunoblot screening on muscle biopsy and Western blot of muscle protein showed a 40% reduction in alpha-sarcoglycan protein (Boito et al., 2003). The c.421 C>A variant was subsequently identified in an individual with severe limb-girdle muscular dystrophy and complete absence of alpha- and delta-sarcoglycan proteins on Western blot of muscle protein who did not have another SGCA pathogenic variant; however, functional characterization of the variant was not performed (Trabelsi et al., 2008). The c.421 C>A variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, but the 1000 Genomes Project reports c.421 C>A was observed in 4/208 (1.9%) alleles from individuals of Puerto Rican background and in 2/1006 (0.2%) alleles from individuals of European background. Several in-silico splice prediction models predict that c.421 C>A creates a cryptic splice donor site which may supplant the natural donor site and lead to abnormal gene splicing. However, in the absence of RNA/functional studies, the actual effect of this sequence change in this individual is unknown. If c.421 C>A does not alter splicing, it will result in the R141S missense change, which is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. Missense variants in nearby residues (E137K/G, L139R) have been reported in the Human Gene Mutation Database in association with SGCA-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. However, this substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV001086384 SCV000649772 likely benign Autosomal recessive limb-girdle muscular dystrophy type 2D 2020-12-05 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000713237 SCV000843823 uncertain significance not provided 2018-04-09 criteria provided, single submitter clinical testing
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 Praxis fuer Humangenetik Tuebingen RCV000713237 SCV001246754 uncertain significance not provided 2020-01-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,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.
Natera, Inc. RCV001086384 SCV001465521 uncertain significance Autosomal recessive limb-girdle muscular dystrophy type 2D 2020-04-03 no assertion criteria provided clinical testing

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