ClinVar Miner

Submissions for variant NM_001018005.2(TPM1):c.337C>G (p.Leu113Val) (rs397516369)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000036327 SCV000059979 likely pathogenic Primary dilated cardiomyopathy 2013-02-11 criteria provided, single submitter clinical testing The Leu113Val variant in TPM1 has not been reported in the literature, but has p reviously been identified by our laboratory in 1 Caucasian infant with DCM. This variant has not been identified in large and broad European American and Africa n American populations by the NHLBI Exome Sequencing Project (http://evs.gs.wash ington.edu/EVS), which increases the likelihood that it is pathogenic. However, we cannot exclude that it may be common in other populations. Leucine (Leu) at a mino acid position 113 is highly conserved across mammals and evolutionarily dis tant species and the change to valine (Val) was predicted to be pathogenic using a computational tool clinically validated by our laboratory. This tool's pathog enic prediction is estimated to be correct 94% of the time (Jordan 2011). In sum mary, this variant is likely pathogenic, though additional studies are required to fully establish its clinical significance.
GeneDx RCV000412875 SCV000490861 likely pathogenic not provided 2016-12-09 criteria provided, single submitter clinical testing The L113V likely pathogenic variant in the TPM1 gene has been previously reported in at least two unrelated families in association with DCM (Pugh et al., 2014; Cuenca et al., 2016). The L113V variant was first reported in a six-month-old Caucasian female with a clinical diagnosis of DCM, who had no history of skeletal myopathy or family history of DCM (Pugh et al., 2014), although further segregation data was not available. This variant was subsequently reported in a Spanish individual with DCM who required a heart transplant at 25 years of age, and segregation studies revealed L113V was also present in three other relatives with DCM, one relative with borderline DCM and one relative with sudden cardiac death at the age of 30 years (Cuenca et al., 2016). Furthermore, the L113V variant 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. Although L113V is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties, this variant occurs at a position that is conserved across species. Moreover, in silico analysis predicts this variant is probably damaging to the protein structure/function.Therefore, this variant is likely pathogenic.
OMIM RCV000736014 SCV000864234 pathogenic Left ventricular noncompaction 9 2019-01-15 no assertion criteria provided literature only

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