Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular Medicine, |
RCV000211870 | SCV000203873 | pathogenic | Hypertrophic cardiomyopathy | 2014-10-06 | criteria provided, single submitter | clinical testing | The Val95Ala variant in TPM1 has been reported in 1 Spanish-American individual with HCM and segregated with disease in >10 affected family members (Karibe 200 1). It was absent from large population studies. In vitro functional studies ind icate this variant may impact protein function (Karibe 2001, Mathur 2011, Bai 20 11, Wang 2011); however, in vitro assays may not accurately represent biological function. Valine (Val) at position 95 is highly conserved in mammals and across evolutionarily distant species and the change to alanine (Ala) was predicted to be pathogenic using a computational tool clinically validated by our laboratory . This tool's pathogenic prediction is estimated to be correct 94% of the time ( Jordan 2011). In summary, this variant meets our criteria to be classified as pa thogenic for HCM in an autosomal dominant manner (http://www.partners.org/person alizedmedicine/LMM) based upon segregation studies, absence from controls, and f unctional evidence. |
| Gene |
RCV000159356 | SCV000209302 | pathogenic | not provided | 2012-06-11 | criteria provided, single submitter | clinical testing | The Val95Ala mutation in the TPM1 gene has been reported previously in association with HCM. Karibe A et al. (2001) reported that the Val95Ala mutation, which was absent from 200 control individuals, co-segregates with HCM in a large family where all 14 individuals with the mutation were affected. Within this family, 11 additional individuals died due to cardiomyopathy suggesting a poor prognosis, despite a mild disease presentation. Although Val95Ala results in a conservative amino acid substitution of one non-polar amino acid with another, the substitution occurs at a position that is highly conserved in vertebrates throughout evolution. Functional study data indicate Val95Ala increases thin filament Ca2+ sensitivity and alters the rate of myosin cycling. Another mutation in a nearby codon (Ile92Thr) has been reported in association with DCM (Hershberger R et al., 2010), further supporting the functional importance of this region of the protein. Val95Ala was not observed in up to 400 alleles in control individuals of African American and Caucasian ancestry tested at GeneDx, indicating it is not a common benign polymorphism in these populations. In summary, Val95Ala in the TPM1 gene is interpreted as a disease-causing mutation. The variant is found in HCM panel(s). |
| Ambry Genetics | RCV000619092 | SCV000740262 | likely pathogenic | Cardiovascular phenotype | 2017-12-14 | criteria provided, single submitter | clinical testing | Strong segregation with disease (lod >3 = >10 meioses);Rarity in general population databases (dbsnp, esp, 1000 genomes) |
| OMIM | RCV000013273 | SCV000033520 | pathogenic | Familial hypertrophic cardiomyopathy 3 | 2001-01-02 | no assertion criteria provided | literature only | |
| Leiden Muscular Dystrophy |
RCV000013273 | SCV000045881 | not provided | Familial hypertrophic cardiomyopathy 3 | 2012-04-15 | no assertion provided | curation |