Submissions for variant NM_014000.3(VCL):c.1403C>T (p.Thr468Met)

gnomAD frequency: 0.00013  dbSNP: rs147957747

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000183998	SCV000236492	uncertain significance	not provided	2024-07-24	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis indicates that this missense variant does not alter protein structure/function
Labcorp Genetics (formerly Invitae), Labcorp	RCV000533986	SCV000645839	uncertain significance	Dilated cardiomyopathy 1W	2024-01-05	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 468 of the VCL protein (p.Thr468Met). This variant is present in population databases (rs147957747, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with VCL-related conditions. ClinVar contains an entry for this variant (Variation ID: 202159). 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. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001290533	SCV001478587	likely benign	not specified	2021-01-14	criteria provided, single submitter	clinical testing	Variant summary: VCL c.1403C>T (p.Thr468Met) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.2e-05 in 251322 control chromosomes. The observed variant frequency is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in VCL causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.1403C>T in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Ambry Genetics	RCV002390474	SCV002697771	uncertain significance	Cardiovascular phenotype	2022-06-06	criteria provided, single submitter	clinical testing	The p.T468M variant (also known as c.1403C>T), located in coding exon 11 of the VCL gene, results from a C to T substitution at nucleotide position 1403. The threonine at codon 468 is replaced by methionine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. The evidence for this gene-disease relationship is limited; therefore, the clinical significance of this alteration is unclear.
Clinical Genetics, Academic Medical Center	RCV000183998	SCV001926131	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000183998	SCV001964209	uncertain significance	not provided		no assertion criteria provided	clinical testing