rs1555420634
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong
The NM_000070.3(CAPN3):c.701G>A(p.Gly234Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,864 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. G234R) has been classified as Uncertain significance.
Frequency
Consequence
NM_000070.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CAPN3 | NM_000070.3 | c.701G>A | p.Gly234Glu | missense_variant | 5/24 | ENST00000397163.8 | |
CAPN3 | NM_024344.2 | c.701G>A | p.Gly234Glu | missense_variant | 5/23 | ||
CAPN3 | NM_173087.2 | c.701G>A | p.Gly234Glu | missense_variant | 5/21 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CAPN3 | ENST00000397163.8 | c.701G>A | p.Gly234Glu | missense_variant | 5/24 | 1 | NM_000070.3 | P2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461864Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4AN XY: 727230
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Autosomal recessive limb-girdle muscular dystrophy type 2A Pathogenic:3
Likely pathogenic, criteria provided, single submitter | research | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Dec 03, 2018 | The heterozygous p.Gly234Glu variant in CAPN3 was identified by our study in the compound heterozygous state, with a likely pathogenic variant, in one individual with limb-girdle muscular dystrophy (LGMD). This variant was absent from large population studies. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro functional studies with a yeast two-hybrid model provide some evidence that the p.Gly234Glu variant may impact protein function by impairing protein binding with substrates (PMID: 9642272). However, these types of assays may not accurately represent biological function. The p.Gly234Glu variant in CAPN3 has been reported in 5 individuals with Limb-Girdle Muscular Dystrophy. The presence of this variant in combination with 4 variants (including a frameshift variant) reported pathogenic by the literature and in 4 of these individuals with LGMD increases the likelihood that the p.Gly234Glu variant is pathogenic (PMID: 16141003, 17994539, 27500519). This variant has also been reported pathogenic in ClinVar (Variation ID: 501754). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PP3, PS3_Moderate, PM3_Strong (Richards 2015). - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 29, 2022 | This missense change has been observed in individuals with clinical features of autosomal recessive limb-girdle muscular dystrophy (PMID: 7720071, 15689361, 16141003, 17994539, 27500519). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects CAPN3 function (PMID: 9642272). 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 CAPN3 protein function. ClinVar contains an entry for this variant (Variation ID: 501754). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 234 of the CAPN3 protein (p.Gly234Glu). - |
Likely pathogenic, no assertion criteria provided | clinical testing | Counsyl | Sep 24, 2017 | - - |
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Feb 23, 2022 | PP3, PM2_SUP, PS3, PM3 - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | May 11, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at