Submissions for variant NM_000070.3(CAPN3):c.1817C>T (p.Ser606Leu)

gnomAD frequency: 0.00004  dbSNP: rs199806879

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000727197	SCV000343724	likely pathogenic	not provided	2016-11-02	criteria provided, single submitter	clinical testing
Invitae	RCV000354372	SCV000828734	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2A	2023-08-31	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 606 of the CAPN3 protein (p.Ser606Leu). This variant is present in population databases (rs199806879, gnomAD 0.03%). This missense change has been observed in individual(s) with autosomal recessive limb-girdle muscular dystrophy (PMID: 9150160, 11245732, 15689361, 15843148, 32576226, 33337384). ClinVar contains an entry for this variant (Variation ID: 289372). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CAPN3 protein function. For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000763349	SCV000894039	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2A; Muscular dystrophy, limb-girdle, autosomal dominant 4	2018-10-31	criteria provided, single submitter	clinical testing
Athena Diagnostics Inc	RCV000727197	SCV001143416	pathogenic	not provided	2019-08-14	criteria provided, single submitter	clinical testing	The best available variant frequency is uninformative because it is below the disease allele frequency. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Occurs in three or more cases with a recessive pathogenic variant in the same gene. Results on protein functions were inconclusive. Moderate co-segregation with disease in affected individuals from a single family.
Revvity Omics, Revvity	RCV000727197	SCV002025056	pathogenic	not provided	2023-11-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003330627	SCV004039561	pathogenic	Autosomal recessive limb-girdle muscular dystrophy	2023-08-16	criteria provided, single submitter	clinical testing	Variant summary: CAPN3 c.1817C>T (p.Ser606Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 251392 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CAPN3 causing Limb-Girdle Muscular Dystrophy, Autosomal Recessive (4.4e-05 vs 0.0032), allowing no conclusion about variant significance. c.1817C>T has been reported in the literature in multiple individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive (Example: Saenz_2005, Richard_1997, Pathak_2021, Jenne_2005). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 15843148, 33337384, 9150160, 15689361). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic.
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV000354372	SCV004047781	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2A		criteria provided, single submitter	clinical testing	The missense variant c.1817C>T (p.Ser606Leu) in CAPN3 gene has been observed in the homozygous state to segregate with limb-girdle muscular dystrophy (LGMD) in a family (Jenne et al. 2005), and in combination with another CAPN3 variant in several individuals affected with LGMD (Sáenz et al. 2005). This variant has been reported to the ClinVar database with conflicting interpretations of pathogenicity as Pathogenic/Likely Pathogenic. This variant is present in the gnomAD exomes database with a frequency of 0.004%. The amino acid Ser at position 606 is changed to a Leu changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by SIFT and PolyPhen2 and the residue is conserved across species. The amino acid change p.Ser606Leu in CAPN3 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic.
Baylor Genetics	RCV003475918	SCV004211506	pathogenic	Muscular dystrophy, limb-girdle, autosomal dominant 4	2023-10-26	criteria provided, single submitter	clinical testing
Counsyl	RCV000354372	SCV000796315	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2A	2017-12-11	no assertion criteria provided	clinical testing