rs1085307995
Variant summary
Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PS1PM1PM2PP3_StrongPP5_Very_Strong
The NM_000070.3(CAPN3):c.985G>A(p.Gly329Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,714 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 nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar. Synonymous variant affecting the same amino acid position (i.e. G329G) has been classified as Likely benign.
Frequency
Consequence
NM_000070.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 20 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CAPN3 | NM_000070.3 | c.985G>A | p.Gly329Arg | missense_variant | 7/24 | ENST00000397163.8 | |
CAPN3 | NM_024344.2 | c.985G>A | p.Gly329Arg | missense_variant | 7/23 | ||
CAPN3 | NM_173087.2 | c.841G>A | p.Gly281Arg | missense_variant | 6/21 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CAPN3 | ENST00000397163.8 | c.985G>A | p.Gly329Arg | missense_variant | 7/24 | 1 | NM_000070.3 | P2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461714Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727162
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Muscular dystrophy, limb-girdle, autosomal dominant 4 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 25, 2024 | - - |
Autosomal recessive limb-girdle muscular dystrophy type 2A Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 11, 2023 | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 329 of the CAPN3 protein (p.Gly329Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal recessive limb-girdle muscular dystrophy (LGMD) (PMID: 21520333, 28915917; 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: 427161). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects CAPN3 function (PMID: 16627476). For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 11, 2015 | The G329R variant was previously reported in a patient with limb-girdle muscular dystrophy type 2A (LGMD2A) who had a second variant on the other allele (CAPN3 LOVD). It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The G329R 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, and multiple missense variants in nearby residues (V320F, Y322H, G333D, H334Y/L/Q) have also been reported in the Human Gene Mutation Database in association with limb-girdle muscular dystrophy (Stenson et al., 2014). 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 a strong candidate for a pathogenic variant, however the possibility that it is a benign variant cannot be excluded. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at