Submissions for variant NM_000070.3(CAPN3):c.1193+6T>A

dbSNP: rs1555421532

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001004974	SCV001164514	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2A	2018-12-03	criteria provided, single submitter	research	The homozygous c.1193+6T>A variant in CAPN3 was identified by our study in one individual with Limb-Girdle Muscular Dystrophy (LGMD). This variant was absent from large population studies. This variant is located in the 5' splice region. Computational tools do not suggest an impact to splicing. However, this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of the c.1193+6T>A variant is uncertain. ACMG/AMP Criteria applied: PM2 (Richards 2015).
CeGaT Center for Human Genetics Tuebingen	RCV001310746	SCV001500663	pathogenic	not provided	2021-01-01	criteria provided, single submitter	clinical testing
Invitae	RCV001004974	SCV002245650	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2A	2023-10-13	criteria provided, single submitter	clinical testing	This sequence change falls in intron 9 of the CAPN3 gene. It does not directly change the encoded amino acid sequence of the CAPN3 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with autosomal recessive limb-girdle muscular dystrophy 2A (LGMD2A) (PMID: 17994539, 20635405). ClinVar contains an entry for this variant (Variation ID: 813980). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in a 31 base pair insertion in intron 9 leading to alternate splicing and introduces a premature termination codon (PMID: 20635405). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003235444	SCV003934038	pathogenic	Autosomal recessive limb-girdle muscular dystrophy	2023-05-04	criteria provided, single submitter	clinical testing	Variant summary: CAPN3 c.1193+6T>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant weakens the canonical 5' donor site. At least one publication reports experimental evidence that this variant affects splicing by inserting 31 base pair in the intron 9 which introduces a premature termination codon (example: Nascimbeni_2010). The variant was absent in 251312 control chromosomes (gnomAD). c.1193+6T>A has been reported in the literature in multiple bi-allelic individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive (example: Guglieri_2008, Nascimbeni_2010, and Fanin_2012). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 17994539, 20635405, 22486197). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic (n=2) and VUS (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
GeneReviews	RCV001004974	SCV002015210	not provided	Autosomal recessive limb-girdle muscular dystrophy type 2A		no assertion provided	literature only	Pathogenic variant most likely the result of a founder effect followed by the Mocheni community in the Fersina River valley in the Italian Alps [Fanin et al 2012].