Submissions for variant NM_003280.3(TNNC1):c.161C>A (p.Pro54His)

dbSNP: rs876661393

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000483835	SCV000565617	likely pathogenic	not provided	2013-01-09	criteria provided, single submitter	clinical testing	The Pro54His variant in the TNNC1 gene has not been reported as a pathogenic variant or as a benign polymorphism to our knowledge. Pro54His results in a non-conservative amino acid substitution of a non-polar Proline with a positively charged Histidine at a position that is conserved across species. In silico analysis predicts Pro54His is possibly damaging to the protein structure/function. Variants in nearby residues (Gln50Arg, Glu59Asp) have been reported in association with cardiomyopathy (Stenson P et al., 2009), further supporting the functional importance of this region of the protein. Furthermore, an external variant database reports Pro54His was not observed in approximately 6,500 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. In summary, while Pro54His is a good candidate for a pathogenic variant, with the clinical and molecular information available at this time we cannot unequivocally determine its clinical significance.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000223755	SCV000280499	uncertain significance	not specified	2013-05-23	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.Pro54His (P54H; c.161 C>A) in the TNNC1 gene. This variant is completely novel, and has not been previously reported as a disease-causing mutation or as a benign polymorphism. Variation at nearby residues in TNNC1 has been associated with cardiomyopathy, potentially supporting the functional importance of this region of the protein: Gln50Arg, Glu59Asp (HGMD via GeneDx). This is a non-conservative amino acid change, resulting in the replacement of a nonpolar proline with a positively-charged histidine. The proline at this location is highly conserved across 43 vertebrate species, differing only in tree shrew (lysine) and megabat (threonine). In silico analysis with PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/) predicts the variant to be “probably damaging” with a score of 0.970. GeneDx reports that its in silico analysis (programs not named) predicts the change to be “possibly damaging”. In total this variant has not been seen in ~6500 individuals from publicly available population datasets. Not many of these individuals are ancestry-matched with our patient, however. (Our patient has Afghani ancestry.) No variation at this codon is present in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~4300 Caucasian and ~2200 African American individuals (as of 2/7/2013). No variation at this codon is present in dbSNP or in 1000 genomes. GeneDx did not report additional controls.