chr17-50168529-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate
The NM_000023.4(SGCA):c.541C>T(p.Arg181Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000305 in 1,576,054 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R181S) has been classified as Uncertain significance.
Frequency
Consequence
NM_000023.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SGCA | NM_000023.4 | c.541C>T | p.Arg181Cys | missense_variant | 5/10 | ENST00000262018.8 | |
SGCA | NM_001135697.3 | c.541C>T | p.Arg181Cys | missense_variant | 5/8 | ||
SGCA | NR_135553.2 | n.577C>T | non_coding_transcript_exon_variant | 5/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SGCA | ENST00000262018.8 | c.541C>T | p.Arg181Cys | missense_variant | 5/10 | 1 | NM_000023.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000158 AC: 24AN: 152134Hom.: 1 Cov.: 32
GnomAD3 exomes AF: 0.0000372 AC: 7AN: 187924Hom.: 0 AF XY: 0.0000399 AC XY: 4AN XY: 100256
GnomAD4 exome AF: 0.0000169 AC: 24AN: 1423802Hom.: 0 Cov.: 33 AF XY: 0.0000156 AC XY: 11AN XY: 704482
GnomAD4 genome AF: 0.000158 AC: 24AN: 152252Hom.: 1 Cov.: 32 AF XY: 0.000215 AC XY: 16AN XY: 74446
ClinVar
Submissions by phenotype
Autosomal recessive limb-girdle muscular dystrophy type 2D Uncertain:5
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 20, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Feb 08, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Aug 10, 2022 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 16, 2022 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 181 of the SGCA protein (p.Arg181Cys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with sarcoglycanopathy (PMID: 12746421). ClinVar contains an entry for this variant (Variation ID: 597557). 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. 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. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 11, 2022 | Variant summary: SGCA c.541C>T (p.Arg181Cys) results in a non-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 0.00016 in 150906 control chromosomes, predominantly at a frequency of 0.0013 within the Latino subpopulation in the gnomAD database, including 1 homozygote. This frequency is somewhat lower than the estimated maximum expected for a pathogenic variant in SGCA causing Autosomal Recessive Limb-Girdle Muscular Dystrophy (0.002), allowing no clear conclusion about variant significance. c.541C>T has been reported in the literature in a compound heterozygous individual who carried a second (likely) pathogenic variant in trans and was affected with muscular dystrophy (Boito_2003). This report does not provide unequivocal conclusions about association of the variant with Autosomal Recessive Limb-Girdle Muscular Dystrophy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all of them classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jun 19, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at