ClinVar Genomic variation as it relates to human health

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).

Variant summary: CAV3 c.277G>A (p.Ala93Thr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00016 in 251184 control chromosomes. This frequency does not allow conclusions about variant significance. c.277G>A has been reported in the literature as a homozygous genotype in families with features of recessive Rippling Muscle Disease and variable phenotypic outcomes ranging from unaffected to mildly affected among obligate carriers (example, Kubisch_2003, Kubisch_2005, Magri_2015, Jacobi_2010). It has also been reported in at-least two individuals (exact zygosity/genotype not specified) in a setting of targeted exome sequencing in a cohort affected by unexplained limb-girdle weakness (example, Topf_2020). 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. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (Pathogenic/Likely pathogenic, n=4; VUS, n=1). Based on the evidence outlined above, the variant was classified as pathogenic.

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 93 of the CAV3 protein (p.Ala93Thr). This variant is present in population databases (rs28936686, gnomAD 0.06%). This missense change has been observed in individual(s) with autosomal recessive limb-girdle muscular dystrophy and autosomal recessive rippling muscle disease (PMID: 12666119, 15668980, 19697367, 27184587). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 8285). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. For these reasons, this variant has been classified as Pathogenic.

CAV3: PM1, PS3:Moderate, PP3, PS4:Supporting

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 the 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 (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). 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 BayesDel analysis. Based on the supporting evidence, this variant is likely to be pathogenic for autosomal recessive caveolinopathy; however, the clinical significance for autosomal dominant caveolinopathy is unclear.

Observed in both the homozygous and heterozygous state in a German family with clinical features of rippling muscle disease. Additionally, reported in the homozygous state in a family member reported to have no muscle weakness, although a physical evaluation was not performed on this individual (PMID: 19697367); Identified in a patient with congenital Long QT syndrome (LQTS) in published literature (PMID: 33614747); Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; Immunohistochemistry and electron microscopy demonstrate loss of caveolin-3 protein and almost complete absence of caveolae in skeletal muscle in an individual homozygous for the p.(A93T) variant (PMID: 12666119); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(A92T); This variant is associated with the following publications: (PMID: 25008241, 15580566, 15668980, 27184587, 19697367, 32419263, 30847666, 25351510, 25630502, 33614747, 32548831, 32528171, Lee2023[article], Leung2023[article], 36556183, 12666119)