Submissions for variant NM_017636.4(TRPM4):c.3073G>A (p.Val1025Ile) (rs186822052)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000477508	SCV000549925	uncertain significance	Progressive familial heart block type 1B	2016-10-23	criteria provided, single submitter	clinical testing	This sequence change replaces valine with isoleucine at codon 1025 of the TRPM4 protein (p.Val1025Ile). The valine residue is moderately conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs186822052, ExAC 0.02%) but has not been reported in the literature in individuals with a TRPM4-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). The isoleucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx	RCV000604033	SCV000724101	likely benign	not specified	2017-11-01	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.