Submissions for variant NM_021625.4(TRPV4):c.1912C>G (p.Pro638Ala) (rs760044422)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000416067	SCV000279738	uncertain significance	not provided	2015-12-23	criteria provided, single submitter	clinical testing	The P638A variant in the TRPV4 gene has been reported previously in a study looking for TRPV4 variants in individuals with inherited neuropathies and control individuals; P638A was detected in a control individual (Fawcett et al., 2012). The P638A 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 P638A 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 that is conserved in mammals. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret P638A as a variant of uncertain significance,
CeGaT Praxis fuer Humangenetik Tuebingen	RCV000416067	SCV000493331	uncertain significance	not provided	2016-08-31	criteria provided, single submitter	clinical testing
Invitae	RCV000687240	SCV000814797	uncertain significance	Charcot-Marie-Tooth disease type 2C	2018-04-17	criteria provided, single submitter	clinical testing	This sequence change replaces proline with alanine at codon 638 of the TRPV4 protein (p.Pro638Ala). The proline residue is moderately conserved and there is a small physicochemical difference between proline and alanine. This variant is present in population databases (rs760044422, ExAC 0.004%). This variant has not been reported in the literature in individuals with TRPV4-related disease. ClinVar contains an entry for this variant (Variation ID: 234727). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.