Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Baylor Genetics | RCV004575490 | SCV005060006 | likely pathogenic | Muscular dystrophy, limb-girdle, autosomal dominant 4 | 2023-11-25 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV004801465 | SCV005423285 | uncertain significance | not specified | 2024-10-14 | criteria provided, single submitter | clinical testing | Variant summary: CAPN3 c.633G>T (p.Lys211Asn) results in a non-conservative amino acid change located in the Peptidase C2, calpain, catalytic domain (IPR001300) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Three predict the variant weakens a 3' acceptor site. In contrast functional studies showed loss of exon 5 in only 5-13% of transcripts in HEK293 cells in vitro (example, Fu_CAPN3_NA_2011), suggesting this variant may not significantly impact splicing. The variant allele was found at a frequency of 4e-06 in 251472 control chromosomes. c.633G>T has been reported in the literature in the presumed compound heterozygous state in at least 1 individual affected with autosomal recessive limb-girdle muscular dystrophy and in the heterozygous state in at least 1 individual with Muscular Dystrophy, Limb-Girdle, Autosomal Dominant 4 (example, Balci_2006, Piluso_2005, Rubegni_2019). Further, a different nucleotide variant resulting in the same protein effect (c.633G>C; p.Lys211Asn) was reported in the heterozygous state in at least 3 individuals with autosomal dominant limb-girdle muscular dystrophy (PMID: 30564623), and an additional variant at this codon with a different protein effect (c.631A>G; p.Lys211Glu) was reported in the presumed heterozygous state in 2 individuals with limb-girdle muscular dystrophy (PMID: 12461690). To our knowledge, no experimental evidence demonstrating an impact on protein function for the c.633G>T p.Lys211Asn variant has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 16411092, 21288883, 16141003, 31517061). ClinVar contains an entry for this variant (Variation ID: 3241004). Based on the evidence outlined above, this variant is classified as VUS-possibly pathogenic. |