Submissions for variant NM_000070.3(CAPN3):c.1194-9A>G

gnomAD frequency: 0.00001  dbSNP: rs374665929

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics	RCV000516175	SCV000255648	pathogenic	not provided	2017-04-28	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000516175	SCV000338518	pathogenic	not provided	2017-10-10	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000201038	SCV000766706	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2A	2023-11-06	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 present in population databases (rs374665929, gnomAD 0.007%). This variant has been observed in individuals with autosomal recessive limb-girdle muscular dystrophy (PMID: 10330340, 11525884, 12461690, 18055493, 22158424, 25135358). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 217146). Studies have shown that this variant results in the retention of 8 nucleotides of intron 9 and introduces a premature termination codon (PMID: 22158424). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV000516175	SCV002018074	pathogenic	not provided	2020-12-22	criteria provided, single submitter	clinical testing
GeneDx	RCV000516175	SCV002102621	pathogenic	not provided	2023-04-24	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect by impairing splicing causing at least a partial intron 9 retention (Salem et al., 2012); This variant is associated with the following publications: (PMID: 25525159, 10330340, 22158424, 33335567, 34720847, 32528171, 31788660, 25135358, 27500519, 30919934, 28403181, 11525884, 26404900)
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV003225933	SCV003922313	pathogenic	Autosomal recessive limb-girdle muscular dystrophy	2023-05-02	criteria provided, single submitter	curation	The heterozygous c.1194-9A>G variant in CAPN3 was identified by our study, in the compound heterozygous state with a pathogenic variant (ClinVar Variation ID: 17622), in one individual with limb-girdle muscular dystrophy. This individual also carried a pathogenic variant (ClinVar Variation ID: 17622), however the phase of these variants are unknown at this time. The c.1194-9A>G variant in CAPN3 has been previously reported in twelve individuals with autosomal recessive limb-girdle muscular dystrophy 1 (PMID: 25135358, PMID: 27066573, PMID: 10330340, PMID: 10330340, PMID: 31788660, PMID: 32528171, PMID: 30919934, PMID: 34720847, PMID: 33335567, PMID: 18055493, PMID: 11525884, PMID: 22158424, PMID: 12461690), segregated with disease in 3 affected relatives from one family (PMID: 22158424), but has been identified in 0.006% (1/16256) of African/African American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs374665929). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 217146) and has been interpreted as pathogenic by PerkinElmer Genomics, Natera, Inc, Athena Diagnostics, Invitae, and Eurofins NTD LLC, and as likely pathogenic by Counsyl and GeneDx. Of these twelve affected individuals previously reported (PMID: 25135358, PMID: 27066573, PMID: 10330340, PMID: 10330340, PMID: 31788660, PMID: 32528171, PMID: 30919934, PMID: 34720847, PMID: 33335567, PMID: 18055493, PMID: 11525884, PMID: 22158424, PMID: 12461690), 6 were homozygotes (PMID: 10330340, PMID: 30919934, PMID: 22158424, PMID: 12461690, PMID: 11525884, PMID: 30919934) , two were compound heterozygotes who carried pathogenic variants in trans (PMID: 25135358, PMID: 31788660), one was a compound heterozygote who carried a likely pathogenic variant in unknown phase (PMID: 18055493), and four were compound heterozygotes who carried variants of uncertain significance in trans (PMID: 25135358, PMID: 27066573, PMID: 34720847), and, in addition, the individual identified by our study was a compound heterozygote who carried a pathogenic variant (ClinVar Variation ID: 17622) in unknown phase, which increases the likelihood that the c.1194-9A>G variant is pathogenic. RT-PCR analysis performed on RNA from an affected individual’s muscle biopsy showed altered splicing, with incorporation of eight nucleotides from intron 9 in a transcript lacking the seven first exons, versus the wild-type transcript seen in RNA from a muscle biopsy of a unaffected control individual (PMID: 22158424). This variant is located in the 3’ splice region. Computational tools do suggest an impact to splicing. However, this information is not predictive enough to determine pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive limb-girdle muscular dystrophy 1. ACMG/AMP Criteria applied: PM3_VeryStrong, PS3_Moderate, PM2_Supporting, PP1 (Richards 2015).
Baylor Genetics	RCV003474967	SCV004211520	pathogenic	Muscular dystrophy, limb-girdle, autosomal dominant 4	2024-03-19	criteria provided, single submitter	clinical testing
Counsyl	RCV000201038	SCV000793873	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2A	2017-09-11	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000201038	SCV001454336	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2A	2020-09-16	no assertion criteria provided	clinical testing