Submissions for variant NM_000023.4(SGCA):c.1A>G (p.Met1Val)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002281872	SCV002572433	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy	2024-10-28	criteria provided, single submitter	clinical testing	Variant summary: SGCA c.1A>G (p.Met1Val) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. A Met codon could not be located several exons downstream. One of two in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 248890 control chromosomes. c.1A>G has been reported in the literature in individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive(1 homozygous patient, Xie_2019). These data indicate that the variant may be associated with disease. Multiple LOF variants located 5 of the next downstream putative in-frame start codon (Met212) have been reported to associate with disease ( c.-1_9del, c.73C>T/p.Q25*, c.234C>A/p.Y78*). Based on the evidence outlined above, the variant was classified as likely pathogenic. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 30764848). ClinVar contains an entry for this variant (Variation ID: 1705242). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003621621	SCV004509432	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2D	2023-03-20	criteria provided, single submitter	clinical testing	This sequence change affects the initiator methionine of the SGCA mRNA. The next in-frame methionine is located at codon 212. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individual(s) with limb girdle muscular dystrophy (PMID: 25135358, 30764848). ClinVar contains an entry for this variant (Variation ID: 1705242). This variant disrupts a region of the SGCA protein in which other variant(s) (p.Leu31Pro) have been determined to be pathogenic (PMID: 9032047, 12566530, 18285821, 22095924, 29351619). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.