Submissions for variant NM_021625.4(TRPV4):c.557G>A (p.Arg186Gln) (rs397514494)

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000235384	SCV000292740	likely pathogenic	not provided	2015-11-01	criteria provided, single submitter	clinical testing	The R186Q variant in the TRPV4 gene has been reported previously in three related individuals with Charcot-Marie-Tooth type 2C (Landouré et al., 2012). R186Q was subsequently reported in an individual with congenital spinal muscular atrophy and arthrogryposis; however, this individual's unaffected mother was a carrier of the variant and the authors concluded that the variant is associated with incomplete penetrance (Echaniz-Laguna et al., 2014). Functional studies show that cells with the R186Q variant had increased cellular toxicity when compared to wild type (Landouré et al., 2012). The R186Q 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 R186Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position where amino acids with similar properties to Arginine are tolerated across species. In silico analysis predicts this variant likely does not alter the protein structure/function. Therefore, the R186Q variant is a strong candidate for a pathogenic variant; however the possibility it may be a rare benign variant cannot be excluded.
Athena Diagnostics Inc	RCV000235384	SCV000615861	pathogenic	not provided	2016-12-02	criteria provided, single submitter	clinical testing
Invitae	RCV000032600	SCV000835712	likely pathogenic	Charcot-Marie-Tooth disease type 2C	2018-04-04	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with glutamine at codon 186 of the TRPV4 protein (p.Arg186Gln). The arginine residue is weakly 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 in an individual affected with congenital spinal muscular atrophy and arthrogryposis (PMID: 24789864) as well as in a family with inherited peripheral neuropathy (PMID: 27549087). This variant has also been reported to segregate with autosomal dominant Charcot-Marie-Tooth disease in a family (PMID: 22675077). ClinVar contains an entry for this variant (Variation ID: 39419). Experimental studies have shown that this missense change, p.Arg186Gln, increases constitutive TRPV4 activity, calcium levels, and cell death in HEK293 cells (PMID: 22675077). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
OMIM	RCV000032600	SCV000056351	pathogenic	Charcot-Marie-Tooth disease type 2C	2014-05-27	no assertion criteria provided	literature only
GeneReviews	RCV000202485	SCV000148049	pathogenic	Neuromuscular Diseases	2014-04-02	no assertion criteria provided	literature only
OMIM	RCV000190887	SCV000245761	pathogenic	Distal spinal muscular atrophy, congenital nonprogressive	2014-05-27	no assertion criteria provided	literature only