chr17-50167430-C-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000023.4(SGCA):c.100C>T(p.Arg34Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 1,614,072 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R34H) has been classified as Pathogenic.
Frequency
Consequence
NM_000023.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SGCA | NM_000023.4 | c.100C>T | p.Arg34Cys | missense_variant | 2/10 | ENST00000262018.8 | |
SGCA | NM_001135697.3 | c.100C>T | p.Arg34Cys | missense_variant | 2/8 | ||
SGCA | NR_135553.2 | n.136C>T | non_coding_transcript_exon_variant | 2/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SGCA | ENST00000262018.8 | c.100C>T | p.Arg34Cys | missense_variant | 2/10 | 1 | NM_000023.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152202Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251428Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135908
GnomAD4 exome AF: 0.0000130 AC: 19AN: 1461870Hom.: 0 Cov.: 32 AF XY: 0.00000963 AC XY: 7AN XY: 727242
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152202Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74364
ClinVar
Submissions by phenotype
Autosomal recessive limb-girdle muscular dystrophy type 2D Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | May 16, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 18, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Dec 31, 2012 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Feb 08, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 04, 2023 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 34 of the SGCA protein (p.Arg34Cys). This variant is present in population databases (rs758647756, gnomAD 0.0009%). This missense change has been observed in individuals with limb-girdle muscular dystrophy (PMID: 9192266, 21031578, 27906075, 32528171). ClinVar contains an entry for this variant (Variation ID: 217250). 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 with a positive predictive value of 95%. This variant disrupts the p.Arg34 amino acid residue in SGCA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7663524, 9032047, 26944168). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 21, 2017 | A variant that is likely pathogenic has been identified in the SGCA gene. The R34C variant has been previously reported in the homozygous state in an individual with severe LGMD2D; parental studies were not performed (Carrie et al., 1997; Eymard et al., 1997). The R34C variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R34C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. Missense variants at the same residue (R34H/L) and in nearby residues (P30L, L31P) have been reported in the Human Gene Mutation Database in association with SGCA-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jul 20, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at