Submissions for variant NM_001032283.3(TMPO):c.565+1728G>C

gnomAD frequency: 0.00188  dbSNP: rs145703021

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000154858	SCV000204540	likely benign	not specified	2012-03-19	criteria provided, single submitter	clinical testing	Val437Leu in exon 4 of TMPO: This variant is not expected to have clinical signi ficance because it has been identified in 0.4% (15/3738) of African American chr omosomes from a broad population by the NHLBI Exome Sequencing Project (http://e vs.gs.washington.edu/EVS; dbSNP rs145703021). Val437Leu in exon 4 of TMPO (rs14 5703021; allele frequency = 0.4%, 15/3738) **
GeneDx	RCV000154858	SCV000236457	benign	not specified	2017-10-23	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.
Invitae	RCV000228189	SCV000287927	benign	Loeys-Dietz syndrome 2	2023-12-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002310719	SCV000318644	likely benign	Inborn genetic diseases	2017-07-20	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000852683	SCV000995392	likely benign	Primary dilated cardiomyopathy	2018-02-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000154858	SCV001432072	benign	not specified	2020-08-31	criteria provided, single submitter	clinical testing	Variant summary: TMPO c.1309G>C (p.Val437Leu) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00047 in 251424 control chromosomes in the gnomAD database, including 1 homozygotes. The observed variant frequency is approximately 19 fold of the estimated maximal expected allele frequency for a pathogenic variant in TMPO causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.1309G>C in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
PreventionGenetics, part of Exact Sciences	RCV003907464	SCV004719418	likely benign	TMPO-related condition	2020-11-10	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).