Submissions for variant NM_000023.4(SGCA):c.307A>G (p.Ile103Val)

gnomAD frequency: 0.00003  dbSNP: rs370819630

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000725508	SCV000337402	likely pathogenic	not provided	2018-05-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001122686	SCV001281432	uncertain significance	Sarcoglycanopathy	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Invitae	RCV000277867	SCV002107650	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2D	2022-07-12	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 103 of the SGCA protein (p.Ile103Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of SGCA-related conditions (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 284685). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant disrupts the p.Ile103Thr amino acid residue in SGCA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9032047, 25135358). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Molecular Genetics, Royal Melbourne Hospital	RCV000277867	SCV002498683	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2D	2021-09-03	criteria provided, single submitter	clinical testing	This sequence change in SGCA is predicted to replace isoleucine with valine at codon 103 (p.(Ile103Val)). The isoleucine residue is highly conserved (100 vertebrates, UCSC), and is located in an extracellular region. There is a small physicochemical difference between isoleucine and valine. The highest population minor allele frequency in gnomAD v2.1 is 0.006% (4/68,020 alleles, 0 homozygotes) in the European (non-Finnish) population, which is consistent with a recessive condition. This variant has been detected with a second pathogenic allele in at least three individuals with limb-girdle muscular dystrophy (PMID: 30564623; LOVD). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (5/6 algorithms). Two other missense variants in the same codon (p.Ile103Thr and p.Ile103Phe) have been reported in cases with limb-girdle muscular dystrophy (PMID: 9032047, 17994539). Based on the classification scheme RMH Modified ACMG Guidelines v1.4.0, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PM3, PM2_Supporting, PP3.
Revvity Omics, Revvity	RCV000277867	SCV003827565	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2D	2023-07-20	criteria provided, single submitter	clinical testing
Counsyl	RCV000277867	SCV000792704	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2D	2019-06-09	no assertion criteria provided	clinical testing