ClinVar Miner

Submissions for variant NM_000023.4(SGCA):c.220C>T (p.Arg74Trp)

gnomAD frequency: 0.00001  dbSNP: rs757888349
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000169146 SCV000958601 pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2D 2023-04-20 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 188811). This missense change has been observed in individual(s) with autosomal recessive limb-girdle muscular dystrophy (LGMD) (PMID: 9455986, 10993494, 15833425, 18285821, 24464767, 30345904; Invitae). 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. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 74 of the SGCA protein (p.Arg74Trp).
Myriad Genetics, Inc. RCV000169146 SCV002060288 likely pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2D 2021-11-15 criteria provided, single submitter clinical testing NM_000023.2(SGCA):c.220C>T(R74W) is a missense variant classified as likely pathogenic in the context of alpha-sarcoglycanopathy. R74W has been observed in cases with relevant disease (PMID: 10993494, 18285821, 9455986, 30345904, 31069529, 29382405). Functional assessments of this variant are not available in the literature. R74W has been observed in population frequency databases (gnomAD: NFE <0.001%). In summary, NM_000023.2(SGCA):c.220C>T(R74W) is a missense variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Genome-Nilou Lab RCV000169146 SCV003931643 likely pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2D 2023-02-08 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003330528 SCV004037735 pathogenic Autosomal recessive limb-girdle muscular dystrophy 2023-08-30 criteria provided, single submitter clinical testing Variant summary: SGCA c.220C>T (p.Arg74Trp) results in a non-conservative amino acid change located in the Dystroglycan-type cadherin-like domain (IPR006644) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 250198 control chromosomes (gnomAD). c.220C>T has been reported in the literature in multiple individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive (examples: Higuchi_1997, Trabelsi_2008, Saha_2018, Ganapathy_2019). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 30345904, 9455986, 31069529, 18285821). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics RCV000169146 SCV004203197 pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2D 2022-11-30 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV000169146 SCV004238641 likely pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2D 2023-05-17 criteria provided, single submitter clinical testing

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