ClinVar Miner

Submissions for variant NM_000232.5(SGCB):c.265G>A (p.Val89Met)

gnomAD frequency: 0.00001  dbSNP: rs762652676
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Limb Girdle Muscular Dystrophy Variant Curation Expert Panel, ClinGen RCV002222588 SCV005620301 likely pathogenic Autosomal recessive limb-girdle muscular dystrophy 2025-01-08 reviewed by expert panel curation The NM_000232.5: c.265G>A variant in SGCB is a missense variant predicted to cause substitution of valine by methionine at amino acid 89 (p.Val89Met). This variant has been detected in at least four individuals with symptoms of limb girdle muscular dystrophy. Of those individuals, one was compound heterozygous for the variant and a pathogenic variant (c.391C>T p.(Arg131Ter), 1 pt, ClinVar SCV000748307.5 internal data communication), and three patients were homozygous for the variant (1 pt, PMID: 28889091, 30838351, 29797799) (PM3_Strong). At least one of these patients displayed progressive limb girdle muscle weakness (PP4). This variant was also shown to co-segregate with autosomal recessive LGMD in one affected family member (PMID: 28889091; PP1). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00003 in the Admixed American population (1/34588 exome alleles), which is lower than the LGMD VCEP threshold (<0.00009) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.932, which is above the threshold of 0.7, evidence that correlates with impact to SGCB function (PP3). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/08/2025): PM3_Strong, PP4, PM2_Supporting, PP3, PP1.
Labcorp Genetics (formerly Invitae), Labcorp RCV000666951 SCV001592853 pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2E 2024-03-11 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 89 of the SGCB protein (p.Val89Met). This variant is present in population databases (rs762652676, gnomAD 0.003%). This missense change has been observed in individual(s) with limb-girdle muscular dystrophy (PMID: 15938573). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 551805). 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 not expected to disrupt SGCB protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002222588 SCV002500418 pathogenic Autosomal recessive limb-girdle muscular dystrophy 2022-03-16 criteria provided, single submitter clinical testing Variant summary: SGCB c.265G>A (p.Val89Met) 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 8e-06 in 251442 control chromosomes (gnomAD). c.265G>A has been reported in the literature in multiple homozygous individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive (e.g. Tasca_2018, Diniz_2017, Yis_2018, Feng_2018). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as pathogenic or as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic.
Revvity Omics, Revvity RCV000666951 SCV003808149 likely pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2E 2023-09-20 criteria provided, single submitter clinical testing
Neuberg Centre For Genomic Medicine, NCGM RCV000666951 SCV004171903 likely pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2E criteria provided, single submitter clinical testing
Baylor Genetics RCV000666951 SCV005056708 likely pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2E 2023-11-25 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000666951 SCV005665319 likely pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2E 2024-03-07 criteria provided, single submitter clinical testing
Counsyl RCV000666951 SCV000791328 uncertain significance Autosomal recessive limb-girdle muscular dystrophy type 2E 2017-05-10 flagged submission clinical testing

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