Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular Medicine, |
RCV000036366 | SCV000060018 | uncertain significance | not specified | 2012-04-24 | criteria provided, single submitter | clinical testing | Variant classified as Uncertain Significance - Favor Pathogenic. The Asn279His v ariant in TPM1 has been identified in homozygosity in 1 proband with RCM tested by our laboratory and has not been identified in large and broad European Americ an and African American populations by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS). This low frequency is consistent with a disease ca using role but insufficient to establish this with confidence. This variant was present in heterozygosity in two family members with HCM but also in a 67 year o ld unaffected family member (this individual). Computational analyses (biochemic al amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not p rovide strong support for or against an impact to the protein. This data support s pathogenicity of the Asn279His variant and raises the possibility that homozyg osity and heterozygosity are associated with different phenotypic outcomes (RCM, HCM). However, the available data is not yet sufficient to conclude this with confidence. |
| Blueprint Genetics | RCV000788149 | SCV000927171 | uncertain significance | not provided | 2017-02-23 | criteria provided, single submitter | clinical testing | |
| Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, |
RCV001256928 | SCV001433449 | uncertain significance | Hypertrophic cardiomyopathy 1 | 2019-10-28 | criteria provided, single submitter | clinical testing | |
| Stanford Center for Inherited Cardiovascular Disease, |
RCV000036366 | SCV000280546 | uncertain significance | not specified | 2011-09-19 | no assertion criteria provided | clinical testing | Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. c.835A>C (p.Asn279His) in the TPM1 gene. We have seen this in a patient with restrictive cardiomyopathy who was homozygous (Caleshu et al 2011). Her father and sister are heterozygous for this variant and are both diagnosed with HCM. Her mother, who also carries one copy of this variant does not have a phenotype of HCM or RCM. In silico analysis with PolyPhen-2 predicts the variant to be benign. The asparagine at codon 279 is conserved across species, as are neighboring amino acids. Other variants have been reported in association with at nearby codons. A variant in a neighboring codon (Met281Thr) has been reported in association with Hypertrophic Cardiomyopathy (van Driest et al 2003) In total the variant has not been seen in ~6,500 published controls and individuals from publicly available population datasets. There is no variation at codon 279 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6,500 Caucasian and African American individuals (as of 5/27/13). This variant was absent in 600 caucasian published controls. Harvard lab did not give control data. There is also no variation at this codon listed in dbSNP or 1000 genomes (as of 5/23/13). |