ClinVar Miner

Submissions for variant NM_000364.4(TNNT2):c.564G>C (p.Leu188Phe) (rs201270895)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000172138 SCV000051076 uncertain significance not provided 2013-06-24 criteria provided, single submitter research
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000036602 SCV000060257 uncertain significance not specified 2011-02-17 criteria provided, single submitter clinical testing The Leu178Phe variant has not been reported in the literature nor detected in is olation by our laboratory. Several organisms (platypus, chicken and frog) natura lly carry a phenylalanine (Phe) at this position, reducing the likelihood that t he change is pathogenic. However, at this time, the available data for the Leu17 8Phe variant is insufficient to definitively exclude a pathogenic role. Therefor e, the clinical significance of this variant cannot be determined at this time.
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000036602 SCV000280529 uncertain significance not specified 2011-07-05 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. p.Leu178Phe (c.534G>C) in the TNNT2 gene. The variant is still novel. I could find no literature reports (as of 3/15/2012). This is a non-conservative amino acid change with a significant change in residue size. However, in silico analysis with PolyPhen-2 predicts the variant to be benign, likely because the leucine at codon 178 is not conserved across species and is in fact a phenylalanine in some species. No other variants have been reported in association with disease at this codon, however a variant at the neighboring codon has been linked to HCM. p.Ser179Phe was observed in a male with severe HCM who was homozygous for the variant and died suddenly at 17 years of age (Ho et al 2000). Three of his siblings died suddenly, one with documented severe HCM. The parents were consanguineous and were confirmed heterozygotes. The mother and her sister (also a heterozygote) both had HCM with a milder phenotype than the children (who were demonstrated or presumed homozygotes). In total the variant has not been seen in 5574 laboratory controls and publicly available population datasets. GeneDx did not observe it in 274 internal control individuals. There is no variation at codon 178 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~5300 Caucasian and African American individuals (as of 3/15/2012). There is also no variation at this codon listed in dbSNP or 1000 genomes (as of 3/15/2012).

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