rs121434548
Variant summary
Our verdict is Pathogenic. Variant got 6 ACMG points: 6P and 0B. PP3PP4PM3PM5
This summary comes from the ClinGen Evidence Repository: The NM_000070.3: c.1469G>A variant in CAPN3 is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 490 (p.Arg440Gln). This variant has been detected in at least 16 individuals with limb girdle muscular dystrophy (PMID:26404900, 18055493, 10330340, 22378277, 22443334, 18854869), including in a homozygous state in at least four cases (1.0 pt; PMID:18055493, 10330340, 22443334) and confirmed in trans with a pathogenic variant in three cases (c.550del p.(Thr184ArgfsTer36), 3.0 pts, PMID:26404900, 18854869, 22378277) (PM3_Very Strong). At least one patient with this variant displayed progressive limb girdle muscle weakness or a clinical suspicion of LGMD (PP4). The highest population minor allele frequency of this variant is 0.0001846 (3/16248 exome alleles) in the African/African American population in gnomAD v2.1.1, which is greater than the LGMD VCEP threshold (<0.0001) for PM2_Supporting (criterion not met). The computational predictor REVEL gives a score of 0.94, which is above the VCEP threshold of 0.70, evidence that correlates with impact to CAPN3 function (PP3). Another missense variant at the same codon, c.1468C>T p.(Arg490Trp), has been classified as pathogenic for autosomal recessive limb girdle muscular dystrophy by the LGMD VCEP (PM5). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/09/2025): PM3_Very Strong, PP4, PP3, PM5. LINK:https://erepo.genome.network/evrepo/ui/classification/CA341479/MONDO:0015152/187
Frequency
Consequence
NM_000070.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| CAPN3 | NM_000070.3 | c.1469G>A | p.Arg490Gln | missense_variant | Exon 11 of 24 | ENST00000397163.8 | NP_000061.1 | |
| CAPN3 | NM_024344.2 | c.1469G>A | p.Arg490Gln | missense_variant | Exon 11 of 23 | NP_077320.1 | ||
| CAPN3 | NM_173087.2 | c.1325G>A | p.Arg442Gln | missense_variant | Exon 10 of 21 | NP_775110.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| CAPN3 | ENST00000397163.8 | c.1469G>A | p.Arg490Gln | missense_variant | Exon 11 of 24 | 1 | NM_000070.3 | ENSP00000380349.3 | ||
| ENSG00000258461 | ENST00000495723.1 | n.*1265G>A | non_coding_transcript_exon_variant | Exon 15 of 26 | 2 | ENSP00000492063.1 | ||||
| ENSG00000258461 | ENST00000495723.1 | n.*1265G>A | 3_prime_UTR_variant | Exon 15 of 26 | 2 | ENSP00000492063.1 |
Frequencies
GnomAD3 genomes 0.0000657 AC: 10AN: 152116Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000677 AC: 17AN: 251152Hom.: 0 AF XY: 0.0000810 AC XY: 11AN XY: 135736
GnomAD4 exome AF: 0.000166 AC: 242AN: 1461808Hom.: 0 Cov.: 32 AF XY: 0.000154 AC XY: 112AN XY: 727200
GnomAD4 genome 0.0000657 AC: 10AN: 152236Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4AN XY: 74434
ClinVar
Submissions by phenotype
Autosomal recessive limb-girdle muscular dystrophy type 2A Pathogenic:8
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with recessive limb-girdle muscular dystrophy 1 (MIM#253600). Dominant negative mechanism is a suggested mechanism for dominant limb-girdle muscular dystrophy 4 (MIM#618129) associated with milder phenotypes and later age of onset (ClinVar, PMID: 27259757). (I) 0108 - This gene is associated with both recessive and dominant disease. It is predominantly reported as a recessive condition, with the dominant condition reported with only a few missense variants and one in-frame deletion (PMID: 27259757, 28881388, 31066050). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 (19 heterozygotes, 0 homozygotes). (SP) 0309 - Multiple alternative amino acid changes at the same position have been observed in gnomAD (v2) (highest allele count: 27 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated calpain large subunit, domain III (DECIPHER). (I) 0703 - Another missense variant comparable to the one identified in this case has moderate previous evidence for pathogenicity. This alternative change (p.(Arg490Trp)) has been reported as pathogenic, and observed in many homozygous and compound heterozygous individuals with a calpainopathy (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times as pathogenic, and observed in homozygous and compound heterozygous individuals with limb girdle muscular dystrophy, and CAPN3-related disorders (ClinVar). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
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The homozygous p.Arg490Gln variant in CAPN3 was identified by our study in one individual with limb-girdle muscular dystrophy (LGMD). This variant has been identified in 0.006860% (19/276950) of chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs121434548). 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 p.Arg490Gln variant in CAPN3 has been reported in 11 individuals with LGMD and segregated with disease in 2 affected relatives from 1 family (PMID: 16971480, 22378277, 16411092). The presence of this variant in combination with 4 variants (2 reported pathogenic, 2 reported in the literature only) and in 5 individuals with LGMD increases the likelihood that the p.Arg490Gln variant is pathogenic (Variation ID: 17621, 289644). In vitro functional studies provide some evidence that the p.Arg490Gln variant may impact protein function by impairing autolytic activity (PMID: 16971480). However, these types of assays may not accurately represent biological function. In summary, this variant meets criteria to be classified as pathogenic for p.Arg490Gln in an autosomal recessive manner based on evidence from function studies and multiple occurrences with pathogenic CAPN3 variants in individuals with hearing loss). ACMG/AMP Criteria applied: PM2, PP3, PP1, PM3_Strong, PS3 (Richards 2015). -
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 490 of the CAPN3 protein (p.Arg490Gln). This variant is present in population databases (rs121434548, gnomAD 0.01%). This missense change has been observed in individual(s) with autosomal recessive limb-girdle muscular dystrophy (PMID: 9266733, 14578192, 15221789, 21984748, 22378277, 27023906, 27431290). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as NM_173087:c.1325G>A. ClinVar contains an entry for this variant (Variation ID: 17622). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt CAPN3 protein function with a positive predictive value of 80%. This variant disrupts the p.Arg490 amino acid residue in CAPN3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7720071, 14578192, 15221789, 16372320, 16971480, 17157502, 18563459, 18854869, 19015733, 19226146, 21204801, 25135358, 25252031, 26632398, 27055500). 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. -
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The observed misssense c.1469G>A(p.Arg490Gln) variant has been reported in homozygous state in multiple patients affected with CAPN3 related disorders (Fanin M, et. al., 2003). Experimental evidence evaluating an impact on protein function demonstrated the variant impairs calpain-3 autolytic activity (Fanin M, et. al., 2007; Fanin M, et. al., 2005). This variant is present with an allele frequency of 0.007% in gnomAD Exomes database. This variant has been reported to the ClinVar database as Likely pathogenic/ Pathogenic (multiple submissions). Multiple lines of computational evidence (Polyphen - probably damaging, SIFT - damaging and MutationTaster -disease causing) predict a damaging effect on protein structure and function for this variant. The reference amino acid is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 490 is changed to a Gln changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. -
not provided Pathogenic:4
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Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 17994539, 18055493, 22378277, 16411092, 16141003, 34440373, 36964972, 36374152, 21984748, 9266733, 15725583, 16650086, 15221789, 10330340, 20635405, 27023906, 27431290, 34426522, 30028523, 32140910, 31589614, 32721234, 32528171, 16971480, 14578192) -
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Autosomal recessive limb-girdle muscular dystrophy Pathogenic:2
Variant summary: CAPN3 c.1469G>A (p.Arg490Gln) results in a conservative amino acid change located in the Calpain subdomain III (IPR033883) of 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 6.8e-05 in 251152 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in CAPN3 causing Limb-Girdle Muscular Dystrophy, Autosomal Recessive (6.8e-05 vs 0.0032), allowing no conclusion about variant significance. c.1469G>A has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive (e.g. Richard_1999, Fanin_2007). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant impairs calpain-3 autolytic activity (Fanin_2007). Seven ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
The NM_000070.3: c.1469G>A variant in CAPN3 is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 490 (p.Arg440Gln). This variant has been detected in at least 16 individuals with limb girdle muscular dystrophy (PMID: 26404900, 18055493, 10330340, 22378277, 22443334, 18854869), including in a homozygous state in at least four cases (1.0 pt; PMID: 18055493, 10330340, 22443334) and confirmed in trans with a pathogenic variant in three cases (c.550del p.(Thr184ArgfsTer36), 3.0 pts, PMID: 26404900, 18854869, 22378277) (PM3_Very Strong). At least one patient with this variant displayed progressive limb girdle muscle weakness or a clinical suspicion of LGMD (PP4). The highest population minor allele frequency of this variant is 0.0001846 (3/16248 exome alleles) in the African/African American population in gnomAD v2.1.1, which is greater than the LGMD VCEP threshold (<0.0001) for PM2_Supporting (criterion not met). The computational predictor REVEL gives a score of 0.94, which is above the VCEP threshold of 0.70, evidence that correlates with impact to CAPN3 function (PP3). Another missense variant at the same codon, c.1468C>T p.(Arg490Trp), has been classified as pathogenic for autosomal recessive limb girdle muscular dystrophy by the LGMD VCEP (PM5). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/09/2025): PM3_Very Strong, PP4, PP3, PM5. -
Muscular dystrophy, limb-girdle, autosomal dominant 4 Pathogenic:1
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Autosomal recessive limb-girdle muscular dystrophy type 2A;C4748295:Muscular dystrophy, limb-girdle, autosomal dominant 4 Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at