ClinVar Miner

Submissions for variant NM_000023.4(SGCA):c.371T>C (p.Ile124Thr)

gnomAD frequency: 0.00003  dbSNP: rs768814872
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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169036 SCV000220189 likely pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2D 2014-03-29 criteria provided, single submitter literature only
Eurofins Ntd Llc (ga) RCV000724041 SCV000229992 pathogenic not provided 2018-04-02 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000169036 SCV000830955 pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2D 2024-10-26 criteria provided, single submitter clinical testing This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 124 of the SGCA protein (p.Ile124Thr). This variant is present in population databases (rs768814872, gnomAD 0.009%). This missense change has been observed in individuals with limb-girdle muscular dystrophy (PMID: 9032047, 10993494, 14595658, 18996010, 19798725). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 188733). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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: 22095924). For these reasons, this variant has been classified as Pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000724041 SCV001448138 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV000169036 SCV002020092 pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2D 2023-04-26 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000169036 SCV002776140 pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2D 2024-03-26 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV000169036 SCV003931663 likely pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2D 2023-02-08 criteria provided, single submitter clinical testing
GeneDx RCV000724041 SCV004031012 pathogenic not provided 2023-08-21 criteria provided, single submitter clinical testing Published functional studies demonstrate that the I124T variant disrupts the membrane localization of the protein (PMID: 31061434); Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 10993494, 30919934, 22095924, 9032047, 18996010, 14595658, 11121445, 9192266, 24742800, 21031578, 30564623, 19781108, 31061434, 19798725)
Neuberg Centre For Genomic Medicine, NCGM RCV000169036 SCV004048273 pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2D criteria provided, single submitter clinical testing The c.371T>C (p.Ile124Thr) variant in SGCA gene has been reported in combination with another SGCA variant in multiple individuals and families affected with limb girdle muscular dystrophy (Fischer et al., 2003; Klinge et al., 2008). Experimental studies have shown that this missense change impairs proper localization of the SGCA protein (Soheili et al., 2012). The p.Ile124Thr variant is reported with the allele frequency (0.002%) in the gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic/Likely Pathogenic. The amino acid Ile at position 124 is changed to a Thr changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid change p.Ile124Thr in SGCA is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV000169036 SCV004203155 pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2D 2024-01-25 criteria provided, single submitter clinical testing
Natera, Inc. RCV000169036 SCV002087564 pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2D 2020-08-03 no assertion criteria provided clinical testing

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