Submissions for variant NM_001018005.2(TPM1):c.389T>C (p.Ile130Thr)

dbSNP: rs727503517

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000152117	SCV000200801	uncertain significance	not specified	2014-04-17	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Pathogenic. The Ile130Thr v ariant in TPM1 has been identified by our laboratory in one individual with DCM (LMM-unpublished data) but was absent from large population studies. Isoleucine (Ile) at position 130 is highly conserved in mammals and across evolutionarily d istant species and the change to Threonine (Thr) was predicted to be pathogenic using a computational tool clinically validated by our laboratory. This tool's p athogenic prediction is estimated to be correct 94% of the time (Jordan 2011). Although the low frequency of this variant and the computational predictions su ggest that it may be pathogenic, additional studies are needed to fully assess i ts clinical significance.
Invitae	RCV000549273	SCV000623803	pathogenic	Hypertrophic cardiomyopathy	2024-01-27	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 130 of the TPM1 protein (p.Ile130Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of dilated cardiomyopathy (Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 165566). 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. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000619274	SCV000737307	uncertain significance	Cardiovascular phenotype	2017-09-13	criteria provided, single submitter	clinical testing	The p.I130T variant (also known as c.389T>C), located in coding exon 4 of the TPM1 gene, results from a T to C substitution at nucleotide position 389. The isoleucine at codon 130 is replaced by threonine, an amino acid with similar properties. Another alteration affecting this amino acid (p.I130V) was detected in a congenital heart defect cohort (England J et al. J. Mol Cell Cardiol. 2017;106:1-13). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV001177591	SCV001341828	uncertain significance	Cardiomyopathy	2023-09-14	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with threonine at codon 130 of the TPM1 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with congenital cardiac anomalies and cardiomyopathy (PMID: 30513141). It has also been reported in individuals affected with dilated cardiomyopathy (ClinVar variation ID: 165566). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
GeneDx	RCV000786231	SCV002512843	uncertain significance	not provided	2022-04-26	criteria provided, single submitter	clinical testing	Reported in a family in which the proband and father expressed phenotypes consistent with Timothy syndrome, and both harbored the c.3717+1_3717+2insA variant in the CACNA1C gene, which was felt to be causative. The proband additionally harbored the I130T variant in the TPM1 gene, which was not observed in the affected father, and the mother did not undergo testing (Bozarth et al., 2018).; Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28359939, 30513141)
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000786231	SCV000924972	uncertain significance	not provided	2017-08-24	no assertion criteria provided	provider interpretation	TPM1, Exon 4, c.389T>C (p.Ile130Thr), heterozygous, Uncertain Significance We have seen this variant in one patient in our center with DCM and a family history of DCM. Given it is rare but with only minimal case data and no segregation data, we consider this variant a variant of uncertain significance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant has been seen in at least one unrelated case of DCM (not including this patient's family). There is so segregation data. LMM has an entry in ClinVar, as a variant of uncertain significance and they note they have seen it in one patient with DCM. There is no variation at codon 130 listed in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Latino, and Ashkenazi descent. The average coverage at that site in gnomAD is >30x.