Submissions for variant NM_000070.3(CAPN3):c.2051-1G>T

dbSNP: rs886042108

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000724152	SCV000331664	pathogenic	not provided	2016-11-02	criteria provided, single submitter	clinical testing
Invitae	RCV000391266	SCV000766715	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2A	2023-11-25	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 18 of the CAPN3 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CAPN3 are known to be pathogenic (PMID: 10330340, 15689361). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with autosomal recessive limb-girdle muscular dystrophy (PMID: 27011640). It is commonly reported in individuals of Indian ancestry (PMID: 23666804, 27011640). ClinVar contains an entry for this variant (Variation ID: 281184). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV000724152	SCV003813118	pathogenic	not provided	2023-09-06	criteria provided, single submitter	clinical testing
Lifecell International Pvt. Ltd	RCV000391266	SCV003922042	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2A		criteria provided, single submitter	clinical testing	A Heterozygous, Splice site acceptor variant c.2051-1G>T in Exon 18 of the CAPN3 gene that results in the amino acid substitution was identified. The observed variant is novel in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic (Variant ID: 281184) . This disorder has previously been reported in the patient affected with muscular dystrophy (Khadilkar SV et al 2018). Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines.
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV000391266	SCV004047120	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2A		criteria provided, single submitter	clinical testing	The splice acceptor variant NM_000070.3(CAPN3) has been reported previously as a Founder mutation in the Aggarwal community (Ankala A et al) and has been described both in homozygous as well as compund heterozygous form with c.2338G>C (p.Asp780His). The variant has been submitted to ClinVar database as Pathogenic. The c.2051-1G>T variant is novel (not in any individuals) in gnomAD and 1000 Genomes. Loss of functon is the known mechanism of the disease (Baralle et al, 2005). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV003475889	SCV004211514	pathogenic	Muscular dystrophy, limb-girdle, autosomal dominant 4	2023-10-22	criteria provided, single submitter	clinical testing
Counsyl	RCV000391266	SCV000792377	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2A	2017-06-21	no assertion criteria provided	clinical testing
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV000391266	SCV000844966	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2A	2018-09-18	no assertion criteria provided	clinical testing	The observed 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. The above variant was observed as compound heterozygous along with the variant c.2338G>C (p.Asp780His). The variant c.2338G>C 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.
GeneReviews	RCV000391266	SCV002015205	not provided	Autosomal recessive limb-girdle muscular dystrophy type 2A		no assertion provided	literature only	Review by ClinVar staff of the sequence in Fig. 2 or Ankala et al 2013 showed that c.2099-1G>T is actually NM_000070.2:c.2051-1G>T.