rs778768583
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PP3_StrongPP5_Very_Strong
The NM_000070.3(CAPN3):c.2338G>C(p.Asp780His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,844 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 Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. D780D) 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 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CAPN3 | NM_000070.3 | c.2338G>C | p.Asp780His | missense_variant | 22/24 | ENST00000397163.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CAPN3 | ENST00000397163.8 | c.2338G>C | p.Asp780His | missense_variant | 22/24 | 1 | NM_000070.3 | P2 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251408Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135860
GnomAD4 exome AF: 0.00000410 AC: 6AN: 1461844Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4AN XY: 727230
GnomAD4 genome ? Cov.: 31
ClinVar
Submissions by phenotype
Autosomal recessive limb-girdle muscular dystrophy type 2A Pathogenic:6Other:1
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Dec 08, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 19, 2023 | This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 780 of the CAPN3 protein (p.Asp780His). This variant is present in population databases (rs778768583, gnomAD 0.003%). This missense change has been observed in individuals with autosomal recessive limb-girdle muscular dystrophy (PMID: 15733273, 23666804, 25079074, 27011640). It is commonly reported in individuals of Agarwal North Indian ancestry (PMID: 15733273, 23666804, 25079074, 27011640). ClinVar contains an entry for this variant (Variation ID: 195641). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CAPN3 protein function. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | research | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Dec 03, 2018 | The heterozygous p.Asp780His variant in CAPN3 was identified by our study in the compound heterozygous state, with another pathogenic variant, in one individual with limb-girdle muscular dystrophy (LGMD). This variant has been identified in 0.0008124% (2/246172) of chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs778768583). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The variant is located in the well-established functional domain EF-hand 4, a domain involved in protein homodimerization (PMID: 24846670). In vitro functional studies with muscle biopsies provide some evidence that the p.Asp780His variant may impact protein function by reducing translation and autolytic activity (PMID: 25079074). However, these types of assays may not accurately represent biological function. The p.Asp780His variant in CAPN3 has been reported in 7 Indian Agarwal individuals with LGMD and is a known founder mutation in the Indian Agarwal community (PMID: 23666804). The presence of this variant in combination with a pathogenic variant by our study as well as a splice site variant in 5 individuals with LGMD increases the likelihood that the p.Asp780His variant is pathogenic (PMID: 23666804). This variant has also been reported pathogenic and likely pathogenic in ClinVar (Variation ID: 195641). In summary, this variant meets criteria to be classified as pathogenic for LGMD in an autosomal recessive manner based on its location in a well-established functional domain and multiple occurrences with other CAPN3 variants. ACMG/AMP Criteria applied: PM2, PP3, PM1, PS3_Supporting, PM3_Strong (Richards 2015). - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Counsyl | Feb 08, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The missense variant c.2338G>Cp.Asp780His in CAPN3 gene has been reported previously in homozygous and compound heterozygous state in multiple individuals with Limb girdle muscular dystrophy Khadlikar et al., 2016, Nilsson MI, et al., 2014. Experimental studies have shown that this missense change results in reduced protein expression and autolytic activity in muscle biopsy samples Nilsson MI et al., 2014. The variant is reported with 0.001% allele frequency in gnomAD and is absent in 1000 Genomes. This variant has been reported to the ClinVar database as Likely Pathogenic/Pathogenic multiple submissions. The variant is predicted to be damaging by SIFT. The amino acid Aspartic acid at position 780 is changed to a Histidine changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics | Sep 18, 2018 | The observed variant c.2338G>C (p.Asp780His) has not been reported in 1000 Genomes and has a minor allele frequency of 0.002% in the ExAC databases. The In silico prediction of the given variant is probably damaging by PolyPhen-2 and damaging by MutationTaster2 and SIFT. The above variant was observed as compound heterozygous along with the variant g.50431G>T (3'splice site). The variant g.50431G>T (3'splice site) has not been reported in 1000 Genomes and ExAC databases. The in silico prediction of the given variant is damaging by MutationTaster2. - |
not provided Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Sep 06, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Sep 02, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Apr 17, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 15, 2018 | The D780H missense variant in the CAPN3 gene has been reported previously as a founder mutation in the Agarwal Eastern Indian population in individuals with LGMD2A (Ankala, et al., 2013; Todorova et al., 2005). In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Additionally, missense variants in nearby residues have been reported in the Human Gene Mutation Database in individuals with limb-girdle muscular dystrophy (Stenson et al., 2014). The D780H variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). Therefore, we interpret D780H as a pathogenic variant. - |
Muscular dystrophy, limb-girdle, autosomal dominant 4 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 19, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at