Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000024575 | SCV000209310 | uncertain significance | not provided | 2018-05-31 | criteria provided, single submitter | clinical testing | A variant of uncertain significance has been identified in the TPM1 gene. The I172T variant was reported as novel in one patient with HCM and a family history of HCM as well as sudden cardiac death (Van Driest et al., 2003). However, this study cohort was screened only for thin filament variants. Subsequently, Van Driest et al. (2004) reported I172T in an individual with HCM who also harbored an MYBPC3 variant, presumably the same patient from the 2003 study due to cohort overlap. Additionally, one functional study suggests that this variant does not impact protein function (Gupte et al., 2015), whereas a more recent functional study suggests this variant may lead to a milder phenotype (Matyushenko et al., 2017). Nevertheless, the I172T variant is not observed in large population cohorts (Lek et al., 2016). This variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Finally, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign. |
| Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, |
RCV000148916 | SCV000747974 | uncertain significance | Primary familial hypertrophic cardiomyopathy | 2017-03-21 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV001314762 | SCV001505306 | uncertain significance | Hypertrophic cardiomyopathy | 2022-05-26 | criteria provided, single submitter | clinical testing | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on TPM1 function (PMID: 25548289, 27983818). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 31879). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 12860912, 15519027, 33673806). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 172 of the TPM1 protein (p.Ile172Thr). |
| Leiden Muscular Dystrophy |
RCV000024575 | SCV000045882 | not provided | not provided | 2012-04-15 | no assertion provided | curation | |
| CSER _CC_NCGL, |
RCV000148916 | SCV000190662 | uncertain significance | Primary familial hypertrophic cardiomyopathy | 2014-06-01 | no assertion criteria provided | research | |
| Blueprint Genetics | RCV000024575 | SCV000927459 | likely pathogenic | not provided | 2017-11-02 | flagged submission | clinical testing |