ClinVar Miner

Submissions for variant NM_033337.2(CAV3):c.277G>A (p.Ala93Thr) (rs28936686)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000234612 SCV000291180 pathogenic Long QT syndrome 2020-10-15 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 93 of the CAV3 protein (p.Ala93Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs28936686, ExAC 0.05%). This variant has been observed in individual(s) with autosomal recessive limb-girdle muscular dystrophy as well as in individuals with autosomal recessive rippling muscle disease (PMID: 27184587, 19697367, 15668980, 12666119). It has also been observed to segregate with disease in related individuals. The study of relatives in one of these families showed that heterozygote carriers present with a much milder phenotype, characterized by subclinical muscle weakness (PMID: 19697367). This variant is also known as c.232G>A (p.Ala92Thr) and c.274G>A (p.Ala92Thr) in the literature. ClinVar contains an entry for this variant (Variation ID: 8285). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C5). For these reasons, this variant has been classified as Pathogenic. 5
GeneDx RCV000024388 SCV000322112 pathogenic not provided 2016-03-15 criteria provided, single submitter clinical testing The A93T pathogenic variant, reported as A92T due to alternative nomenclature, was initially identified in one homozygous patient with rippling muscle disease (RMD), phenotype limited to skeletal muscle, without cardiac involvement (Kubisch et al., 2003). Immunohistochemistry and electron microscopy demonstrated a loss of caveolin-3 protein and almost complete absence of caveolae in skeletal muscle of this homozygous individual (Kubisch et al., 2003). Subsequently, two siblings with RMD were also found to be homozygous for the pathogenic variant, while their asymptomatic parents were heterozygous for the variant, suggesting an autosomal recessive form of RMD (Kubisch et al., 2005). However, in another reported family both homozygous and heterozygous carriers of the A93T variant presented with a spectrum of clinical features associated with RMD (Jacobi et al., 2010). The A93T variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The A93T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. We interpret A93T as a pathogenic variant.
Ambry Genetics RCV000622234 SCV000737718 uncertain significance Cardiovascular phenotype 2020-09-30 criteria provided, single submitter clinical testing The p.A93T variant (also known as c.277G>A), located in coding exon 2 of the CAV3 gene, results from a G to A substitution at nucleotide position 277. The alanine at codon 93 is replaced by threonine, an amino acid with similar properties. This alteration (also known as p.A92T) has been reported in a homozygous state in individuals with rippling muscle disease (RMD) and limb-girdle muscular dystrophy, and one study indicated reduction of CAV3 protein expression and caveolae in skeletal muscle from a homozygous individual (LGMD) (Kubisch C et al. Ann. Neurol., 2003 Apr;53:512-20; Kubisch C et al. Ann. Neurol., 2005 Feb;57:303-4; Magri F et al. Muscle Nerve, 2016 May). In one family, heterozygous individuals did not exhibit any symptoms of RMD, while another family demonstrated mild symptoms of muscle weakness in heterozygous family members (Kubisch C et al. Ann. Neurol., 2005 Feb;57:303-4; Jacobi C et al. Muscle Nerve, 2010 Jan;41:128-32). In addition, an individual homozygous for this alteration was self-reported to be asymptomatic (Jacobi C et al. Muscle Nerve, 2010 Jan;41:128-32). This variant was also described in a late onset vacuolar myopathy cohort, as seen in a heterozygous proband with elevated serum CK levels and in his heterozygous mother with polyneuropathy; no cardiac findings were reported (Mair D et al. Brain Pathol., 2020 Sep;30:877-896). This variant has also been reported in hypertrophic cardiomyopathy and dilated cardiomyopathy genetic testing cohorts; however, clinical details were limited and additional variants were detected in some cases (Lopes LR et al. Heart, 2015 Feb;101:294-301; van Lint FHM et al, 2019 Jun;27:304-309). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000024388 SCV000855726 pathogenic not provided 2017-07-12 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000826098 SCV000967603 likely pathogenic Rippling muscle disease 2 2018-02-02 criteria provided, single submitter clinical testing The p.Ala93Thr variant in CAV3 has been reported in the homozygous state in 3 in dividuals with clinical features of rippling muscle disease and segregated with disease in 1 affected family member (Kubisch 2003, Kubisch 2005, Jacobi 2010). I n one family, both heterozygous parents as well as a heterozygous sibling were m ildly affected. Another homozygous sibling reported no features but this was no t confirmed clinically (Jacobi 2010). This variant has been identified in 0.02% (25/126586) of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs28936686). Studies in patient muscle c ells show a reduction or absence of the CAV3 protein (Kubisch 2003, Kubisch 2005 ). This variant has also been reported in ClinVar (8285). In summary, although a dditional studies are required to fully establish its clinical significance, the p.Ala93Thr variant is likely pathogenic. ACMG/AMP Criteria applied: PS3_Moderat e, PP1_Moderate, PP3, PS4_Supporting (Richards 2015).
OMIM RCV000008780 SCV000028990 pathogenic Rippling muscle disease 2, autosomal recessive 2005-02-01 no assertion criteria provided literature only
Leiden Muscular Dystrophy (CAV3) RCV000024388 SCV000045682 not provided not provided 2012-04-15 no assertion provided curation

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