TPM1 : c.712C>T

Variant Details

Variant (CDS)Variant (protein)Variant Type Variant EffectGenomic Location (GRCh37)ExAC Frequency
c.712C>Tp.R238W (Arg > Trp)substitutionmissense chr15:63354784 (forward strand)0.000000

Effect in Cardiac Disease

This variant is considered a rare variant and is not detected in the ExAC population database (>60,000 samples).

HCM

Rare TPM1 Non-Truncating variants are significantly enriched in HCM (details) and have an etiological fraction (EF) of 0.94.

OMGL: Detected in 0 / 1535 HCM patients.

LMM:   Detected in 0 / 2912 HCM patients.

DCM

Rare TPM1 Non-Truncating variants are significantly enriched in DCM (details) and have an etiological fraction (EF) of 0.95.

OMGL: Detected in 0 / 355 DCM patients.

LMM:   Detected in 1 / 756 DCM patients - classified as VUS favour pathogenic.

The EF is the estimated proportion of rare variants of this class that will be pathogenic in a cardiomyopathy proband, a prior probability based solely on variant frequency data in cases and controls, and should be further refined by additional evidence such as family segregation data, known association with disease, population frequency, protein domain analysis, functional studies and in silico algorithms to assess the significance of a variant.

For more information on the clinical significance of this variant, please see the ClinVar entry.

Detection in Population Databases

This variant has not been detected in the ExAC Aggregation Consortium (ExAC) database (>60,000 samples), the 1000 Genomes (1KG) database (2,500 samples) or the Exome Sequencing Project (ESP) database (6,500 samples).

The Exome Aggregation Consortium (ExAC) is a database of 60,706 unrelated individuals sequenced as part of various disease-specific and population genetic studies. There is partial overlap between ExAC and 1000 Genomes (1KG) (1,851 of the 2,504 samples in 1KG) and the Exome Sequencing Project (ESP) (3,936 of the 6,500 samples in ESP).


Other Variant & Gene Details

Canonical Sequences
Transcript ENST00000403994 LRG_387t1NM_001018005.1
Protein ENSP00000385107 LRG_387p1

Missense Variant Predictions
SIFT Grantham Polyphen-DIV Polyphen-VAR Summary
100% of algorithms have predicted that this variant will adversely affect protein function
damaging moderately radical probably damaging probably damaging
LRT MutationTaster MutationAssessor FATHMM
deleterious disease-causing high impact damaging


References

1. Roddy Walsh, Kate L. Thomson, James S. Ware, Birgit H. Funke, Jessica Woodley, Karen J. McGuire, Francesco Mazzarotto, Edward Blair, Anneke Seller, Jenny C. Taylor, Eric V. Minikel, Exome Aggregation Consortium, Daniel G. MacArthur, Martin Farrall, Stuart A. Cook and Hugh Watkins. Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples. Genet Med. 2016 doi:10.1038/gim.2016.90.

2. Pugh TJ, Kelly MA, Gowrisankar S, Hynes E, Seidman MA, Baxter SM, Bowser M, Harrison B, Aaron D, Mahanta LM, Lakdawala NK, McDermott G, White ET, Rehm HL, Lebo M, Funke BH. The landscape of genetic variation in dilated cardiomyopathy as surveyed by clinical DNA sequencing. Genet Med. 2014 Aug;16(8):601-8.

3. Alfares AA, Kelly MA, McDermott G, Funke BH, Lebo MS, Baxter SB, Shen J, McLaughlin HM, Clark EH, Babb LJ, Cox SW, DePalma SR, Ho CY, Seidman JG, Seidman CE, Rehm HL. Results of clinical genetic testing of 2,912 probands with hypertrophic cardiomyopathy: expanded panels offer limited additional sensitivity. Genet Med. 2015 Nov;17(11):880-8.