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

gnomAD frequency: 0.00001  dbSNP: rs116840778

Total submissions: 15

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
Eurofins Ntd Llc (ga)	RCV000408119	SCV000338152	pathogenic	not provided	2017-02-24	criteria provided, single submitter	clinical testing
Invitae	RCV000527324	SCV000627777	pathogenic	Long QT syndrome	2023-12-18	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
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