ClinVar Miner

Submissions for variant NM_033337.2(CAV3):c.80G>A (p.Arg27Gln) (rs116840778)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000408119 SCV000329203 pathogenic not provided 2018-05-09 criteria provided, single submitter clinical testing The R27Q pathogenic variant in the CAV3 gene has been reported previously in multiple individuals in a family with autosomal dominant rippling muscle disease (RMD), limb-girdle muscular dystrophy type 1C (LGMD1C), or a combination of both conditions (Fee et al., 2004). The R27Q pathogenic variant has also been reported as a de novo variant in two unrelated individuals with hyperCKemia (Carbone et al., 2000; CAV3 LOVD). Functional studies have shown that R27Q decreases nerve and epidermal growth factor signaling (Brauers et al., 2010). In those studies, R27Q was reported as R26Q due to the use of alternative nomenclature. The R27Q pathogenic variant was not observed in approximately 6,500 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 R27Q pathogenic variant alters a conserved position predicted to be within the N-terminal cytoplasmic domain, and several pathogenic variants (R27G, D28E, P29T, and P29L) have been reported in nearby residues, in association with caveolinopathies (Stenson et al., 2014). Therefore, we interpret R27Q as a pathogenic variant, and its presence is consistent with a diagnosis of a CAV3-related disorder
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000408119 SCV000338152 pathogenic not provided 2017-02-24 criteria provided, single submitter clinical testing
Invitae RCV000527324 SCV000627777 pathogenic Long QT syndrome 2020-09-09 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 27 of the CAV3 protein (p.Arg27Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with disease in families affected with autosomal dominant rippling muscle disease and distal myopathy (PMID: 15318349, 18930476, 12807393). This variant has also been reported in the heterozygous state in unrelated individuals affected with phenotypes including rippling muscle disease, limb-girdle muscular dystrophy type 1C, distal myopathy, and hyperCKemia (PMID: 20472890, 12939441, 21404291, 11805270, 18583131, 15580566, 11431690). In several affected individuals this variant was reported to arise de novo (PMID: 10746614, 11756609). ClinVar contains an entry for this variant (Variation ID: 8283). Experimental studies have shown that this missense change causes mislocalization of the caveolin-3 protein to the Golgi apparatus instead of the plasma membrane (PMID: 12839838). Additional studies have shown that this variant also disrupts the interaction between caveolin-3 and other proteins in the sarcolemma and dystrophin-glycoprotein complex (PMID: 20472890, 14633633, 19380584). For these reasons, this variant has been classified as Pathogenic.
SIB Swiss Institute of Bioinformatics RCV000008778 SCV000803482 pathogenic Rippling muscle disease 2 2018-05-31 criteria provided, single submitter curation This variant is interpreted as a Pathogenic, for Caveolinopathies (creatine phosphokinase, elevated serum. HyperCKemia. Rippling muscle disease 2 (RMD2). Myopathy, distal, Tateyama type (MPDT). Limb-girdle muscular dystrophy 1C (LGMD1C)), in Autosomal Dominant manner. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PM6 => Assumed de novo, but without confirmation of paternity and maternity (PMID:10746614). PS2 => De novo (paternity and maternity confirmed) (PMID:11756609). PS3 => Well-established functional studies show a deleterious effect (PMID:12939441) (PMID:15580566). PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS4-Moderate => PS4 downgraded in strength to Moderate.
Athena Diagnostics Inc RCV000408119 SCV000841370 pathogenic not provided 2018-06-22 criteria provided, single submitter clinical testing Not found in the total gnomAD dataset, and the data is high quality. Predicted to have a damaging effect on the protein. Assessment of experimental evidence suggests this variant results in abnormal protein function. Very strong co-segregation with disease. However, available data lack unaffected family members. One de novo case with parental identity confirmed.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000408119 SCV001248494 pathogenic not provided 2019-03-01 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000408119 SCV001715805 pathogenic not provided 2020-11-02 criteria provided, single submitter clinical testing PS3, PS4, PM2, PP1, PP3, PP4
OMIM RCV000008778 SCV000028985 pathogenic Rippling muscle disease 2 2009-01-15 no assertion criteria provided literature only
OMIM RCV000008777 SCV000028986 pathogenic Elevated serum creatine phosphokinase 2009-01-15 no assertion criteria provided literature only
OMIM RCV000023083 SCV000044374 pathogenic Distal myopathy, Tateyama type 2009-01-15 no assertion criteria provided literature only
Leiden Muscular Dystrophy (CAV3) RCV000023083 SCV000045677 not provided Distal myopathy, Tateyama type 2012-04-15 no assertion provided curation
Institute of Human Genetics, Klinikum rechts der Isar RCV000023083 SCV001430063 pathogenic Distal myopathy, Tateyama type 2020-03-13 no assertion criteria provided clinical testing

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