Submissions for variant NM_004621.6(TRPC6):c.2299G>A (p.Val767Met)

gnomAD frequency: 0.00001  dbSNP: rs200772226

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001103187	SCV001259912	benign	Focal segmental glomerulosclerosis 2	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002555006	SCV003292987	uncertain significance	not provided	2022-11-15	criteria provided, single submitter	clinical testing	This variant has not been reported in the literature in individuals affected with TRPC6-related conditions. This variant is present in population databases (rs200772226, gnomAD 0.07%), and has an allele count higher than expected for a pathogenic variant. This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 767 of the TRPC6 protein (p.Val767Met). ClinVar contains an entry for this variant (Variation ID: 877461). 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TRPC6 protein function.
Revvity Omics, Revvity	RCV001103187	SCV003821528	uncertain significance	Focal segmental glomerulosclerosis 2	2019-12-16	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003283978	SCV003955130	uncertain significance	Inborn genetic diseases	2023-03-23	criteria provided, single submitter	clinical testing	The c.2299G>A (p.V767M) alteration is located in exon 9 (coding exon 9) of the TRPC6 gene. This alteration results from a G to A substitution at nucleotide position 2299, causing the valine (V) at amino acid position 767 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.