Submissions for variant NM_033337.3(CAV3):c.80G>A (p.Arg27Gln)

gnomAD frequency: 0.00001  dbSNP: rs116840778

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000408119	SCV000329203	pathogenic	not provided	2024-10-24	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect and suggest that this variant was prevented from reaching normal plasma membrane levels and was not enough to prevent leakage of CK to the serum (PMID: 12839838); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; Also known as p.(R26Q); This variant is associated with the following publications: (PMID: 20472890, 11532985, 12939441, 21404291, 11756609, 12807393, 30723005, 35531120, 31036801, 25630502, 30174172, 28981925, 32528171, 15318349, 10746614, 12839838)
Eurofins Ntd Llc (ga)	RCV000408119	SCV000338152	pathogenic	not provided	2017-02-24	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000527324	SCV000627777	pathogenic	Long QT syndrome	2025-01-11	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 27 of the CAV3 protein (p.Arg27Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with distal myopathy, hyperCKemia, limb-girdle muscular dystrophy type 1C, and/or rippling muscle disease (PMID: 10746614, 11431690, 11756609, 11805270, 12807393, 12939441, 15318349, 15580566, 18583131, 18930476, 20472890, 21404291). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 8283). 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. Experimental studies have shown that this missense change affects CAV3 function (PMID: 12839838, 14633633, 19380584, 20472890). 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	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 Center for Human Genetics Tuebingen	RCV000408119	SCV001248494	pathogenic	not provided	2019-03-01	criteria provided, single submitter	clinical testing
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000023083	SCV001430063	pathogenic	Distal myopathy, Tateyama type	2020-03-13	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
Revvity Omics, Revvity	RCV000408119	SCV002016931	pathogenic	not provided	2020-10-26	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000008778	SCV002581137	pathogenic	Rippling muscle disease 2	2022-08-26	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002490340	SCV002783793	pathogenic	Elevated circulating creatine kinase concentration; Hypertrophic cardiomyopathy 1; Long QT syndrome 9; Rippling muscle disease 2; Distal myopathy, Tateyama type	2021-07-26	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000023083	SCV005200107	pathogenic	Distal myopathy, Tateyama type	2024-08-27	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000008778	SCV005394004	pathogenic	Rippling muscle disease 2	2024-09-04	criteria provided, single submitter	clinical testing	Variant summary: CAV3 c.80G>A (p.Arg27Gln) results in a 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 frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.80G>A has been reported in the literature in multiple heterozygous individuals affected with Rippling Muscle Disease 2, Limb-Girdle Muscular Dystrophy Type 1C, or HyperCKemia (e.g. Vorgerd_2001, Carbone_2000, Fee_2004). In some individuals, the variant was observed to be de novo. These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in reduced nerve growth factor signaling in transfected cells (Brauers_2010). The following publications have been ascertained in the context of this evaluation (PMID: 20472890, 10746614, 15318349, 11756609). ClinVar contains an entry for this variant (Variation ID: 8283). Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000008778	SCV000028985	pathogenic	Rippling muscle disease 2	2009-01-15	no assertion criteria provided	literature only
OMIM	RCV000008777	SCV000028986	pathogenic	Elevated circulating creatine kinase concentration	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