Submissions for variant NM_001018005.2(TPM1):c.712C>T (p.Arg238Trp)

dbSNP: rs397516386

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000159384	SCV000209330	likely pathogenic	Cardiomyopathy	2014-07-15	criteria provided, single submitter	clinical testing	The R238W variant in the TPM1 gene has been reported as a "pathogenic variant" in a publication investigating the technical sensitivity of a mutation detection assay. Clinical information associated with R238W was not included in this publication (Zimmerman R et al., 2010). R238W is a non-conservative amino acid substitution as these residues differ in polarity, charge, size and/or other properties and is more likely to impact secondary structure. The R238 residue is conserved across species. Mutations in nearby residues (D230N, A239T) have been reported in association with DCM, further supporting the functional importance of this region of the protein. Furthermore, R238W 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. Therefore, this variant is a strong candidate for a pathogenic mutation, however the possibility that it is a benign variant cannot be excluded. The variant is found in CARDIOMYOPATHY panel(s).
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036356	SCV000060008	uncertain significance	not specified	2008-03-01	no assertion criteria provided	clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000036356	SCV000280544	uncertain significance	not specified	2013-05-27	no assertion criteria provided	clinical testing	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Arg238Trp (R238W; c.712 C>T) in exon 8 of the TPM1 gene The testing lab refered to it as “published” because after being seen at LMM it was added to a DCM sequencing chip in a publication by Zimmerman et al. (2010) as a “pathogenic variant” (this is the group from LMM and Partners Healthcare; see the paper’s supplementary material). Because of this same reference, it is listed in HGMD. There is no segregation data available. This is a non-conservative amino acid change, resulting in the replacement of a positively-charged Arginine with a nonpolar Tryptophan. The Arginine at this location is highly conserved across 10 vertebrate species for which information is available. Several adjacent residues on either side are also highly conserved. Variation at nearby residues has been associated with cardiomyopathy, which supports the functional importance of this region of the protein: Asp230Asn, Ala239Thr (HGMD professional version as of January 17, 2014). In silico analysis with PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/) predicts the variant to be “probably damaging” with a score of 1.0. In total the variant has not been seen in ~6500 individuals from publicly available population datasets. This variant is not listed in the NHLBI Exome Sequencing Project dataset (http://evs.gs.washington.edu/EVS/), which currently includes variant calls on ~4300 Caucasian and ~2200 African American individuals. However, these individuals are not ancestry-matched to our patient, who is of Mexican descent. The phenotype of the ESP individuals is not publicly available, however the cohorts that were merged to create this dataset were all either general population samples or samples recruited for common cardiovascular disease such as hypertension. There is also no variation at this codon listed in dbSNP (http://www.ncbi.nlm.nih.gov/projects/SNP) or 1000 genomes (http://browser.1000genomes.org/index.htm) as of April 15, 2014.