Submissions for variant NM_000070.3(CAPN3):c.742_743del (p.Met248fs)

dbSNP: rs1064793620

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000482838	SCV000566616	likely pathogenic	not provided	2017-06-20	criteria provided, single submitter	clinical testing	The c.742_743delAT variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The c.742_743delAT variant causes a frameshift starting with codon Methionine 248, changes this amino acid to a Valine residue and creates a premature Stop codon at position 19 of the new reading frame, denoted p.Met248ValfsX19. This variant is predicted to cause loss of normal protein function through protein truncation or nonsense-mediated mRNA decay. Although this variant has not been reported previously to our knowledge, other loss-of-function variants in the CAPN3 gene have been reported in the Human Gene Mutation Database in association with LGMD2A (Stenson et al., 2014).
Invitae	RCV000821006	SCV000961745	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2A	2018-10-30	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Met248Valfs*19) in the CAPN3 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in CAPN3 are known to be pathogenic (PMID: 10330340, 15689361). This variant has not been reported in the literature in individuals with CAPN3-related disease. ClinVar contains an entry for this variant (Variation ID: 419065).