Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000248954 | SCV000318080 | pathogenic | Cardiovascular phenotype | 2017-02-27 | criteria provided, single submitter | clinical testing | ​The p.Q175* mutation (also known as c.523C>T), located in coding exon 7 of the TNNI3 gene, results from a C to T substitution at nucleotide position 523. This changes the amino acid from a glutamine to a stop codon within exon 7. This alteration has been determined to be the result of a likely de novo event in one proband with restrictive cardiomyopathy (RCM) tested in our laboratory. Although the mechanism of disease for this gene is not completely understood, other truncating alterations in TNNI3 have been reported in patients with restrictive cardiomyopathy (RCM) and hypertrophic cardiomyopathy (HCM) (Kaski JP et al. Heart. 2008;94(11):1478-84; Kostareva A et al. Int J Cardiol. 2009;131(3):410-2; Olivotto I et al. J Am Coll Cardiol. 2011;58(8):839-48; van den Wijngaard A et al. Neth Heart J. 2011;19(7-8):344-51). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
| Stanford Center for Inherited Cardiovascular Disease, |
RCV000223834 | SCV000280511 | likely pathogenic | not provided | 2013-08-06 | 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.Gln175Stop (Q175X; c.523 C>T) in the TNNI3 gene The p.Q175X variant is located in exon 7 out of 8 in the TNNI3 gene. According to the testing lab the majority (85%) of mutations in TNNI3 (which encodes troponin I) have been identified in exons 7 and 8, which encode domains that interact with cardiac actin (ACTC1) and cardiac troponin C (TNNC1). Based on the information reviewed here, we initially classified it as a Variant of Unknown Significance (VUS), then upgraded it to likely disease causing when it was found to be de novo in our patient (with unaffected parents). To date, it is not clear that premature stop codons in the gene TNNI3 typically cause disease. According to the testing lab of the 67 total TNNI3 alterations reported in the Human Gene Mutation Database (HGMD), only 1 is a nonsense alteration leading to a premature stop codon. However, frameshift alterations resulting in premature stop codons and splicing variants have also been reported in HGMD. Per the testing lab: "In one study, c.4762delG was detected in a patient with restrictive cardiomyopathy (RCM) (Kostareva et al. 2009 Int J Cardiol 131(3):410-2). In another study, a de novo frameshift alteration (c.4789_4790delAA) was detected in a patient diagnosed with RCM at age 6 years (Kaski et al. 2008 Heart 94:1478–1484). Another study detected a frameshift alteration (c.257_258del) in a 26-year-old female diagnosed with hypertrophic cardiomyopathy with a maximum left ventricular wall thickness of 27mm. However, this patient also had alterations in MYBPC3 (c.772G>A) and in MYH7 (c.2606G>A) (Olivotto et al. 2011 J Am Coll Cardiol 58:839–48). In another study, a de novo alteration occurring at the 5' splice consensus sequence in intron 7 was detected in a female patient diagnosed with RCM at less than 1 year of age (Van den Wijngaard et al. 2011 Neth Heart J 19:344–351)." The p.Gln175Stop alteration was not reported in population-based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. However, other truncating mutations have been found in these general-population cohorts. There is one frameshift variant for TNNI3 listed in the Exome Variant server, seen in 3/7836 Caucasian and 1/3614 African American alleles. 1000 Genomes contains no stop gained mutations for TNNI3, but lists a frameshift variant from dbSNP: rs35173650. p.R98X was detected in a 71-year-old male patient from the Framingham Heart Study cohort (Bick et al. 2012 Am J Hum Genet 91:513–519). p.Leu348Arg (L348R; c.1043 T>G) in the ABCC9 gene This is a non-conservative amino acid change from a nonpolar leucine to a positively-charged arginine at an amino acid residue that is well-conserved (and always nonpolar) across vertebrate species. Ambry reports that it is predicted to be “probably damaging” and “tolerated” by PolyPhen and SIFT in silico analyses, respectively. This variant is not present in population-based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP) and 1000 Genomes ProjectSince supporting evidence is limited at this time, the clinical significance of p.L348R remains unclear. Ambry reports that autosomal dominant, typically de novo, missense mutations in ABCC9 (NM_005691.2) have been reported to cause Cantú syndrome, a condition characterized by congenital hypertrichosis, distinctive facial features and cardiac defects (Harakalova et al. 2012. Nat Genet 44(7):793-6). In addition, heterozygous missense mutations in exon 38 (the exon unique to SUR2A) have been reported to cause dilated cardiomyopathy and atrial fibrillation (Bienengraeber et al. 2004 Nat Genet 36(4):382-387; Olson et al. 2007 Nat Clin Pract Cardiovasc Med 4(2):110-116). Caleb’s variant is located in exon 7. p.Leu1161Ile (L1161I; c.3481 C>A) in the MYPN gene This is a conservative amino acid change from nonpolar leucine to a nonpolar isoleucine at a residue that is highly conserved across vertebrate species (it is a nonpolar phenylalanine in squirrel). It is predicted to be “probably damaging” and “tolerated” by PolyPhen and SIFT in silico analyses, respectively. By Ambry’s report, p.L1161I has been identified in a patient with cardiomyopathy as well as in controls. In one study, p.L1161I was identified in a male patient who was diagnosed with hypertrophic cardiomyopathy (HCM) with an onset at 46 years. This patient did not have a family history of HCM and his ethnicity was reported to be American Indian/Alaskan. This variant was previously reported in the SNPDatabase as rs138313730. Based on data from the NHLBI Exome Sequencing Project (ESP), the A-allele has an overall frequency of approximately 0.03% (3/10,755), having been observed in 0% (0/3,738) of African American alleles, and in 0.04% (3/7,020) of European American alleles. Based on data from the 1000 Genomes Project, the A-allele has an overall frequency of approximately 0.23% (5/2,188). The highest observed frequency was 2 of 178 (1.12%) Japanese chromosomes. Since supporting evidence is limited at this time, the clinical significance of p.L1161I remains unclear. MYPN (NM_032578.2) encodes myopalladin, a protein component of the sarcomere. Heterozygous mutations in MYPN have been reported in hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM) and restrictive cardiomyopathy (RCM) (Purevjav et al. 2012 Hum Molec Genet 21(9):2039-2053; Meyer et al. 2012 Eur J Hum Genet Epub ahead of print). p.Ile27514Met (I27514M; c.82542 A>G) in the TTN gene Testing also found a missense TTN variant that Ambry classified as suspected benign. It is unclear at this time what role, if any, TTN missense variants (or in-frame deletions) play in causing inherited cardiomyopathy. In general-population samples there is a high prevalence of rare or novel TTN missense variants, making it likely that testing anyone with this panel would uncover such a variant (Herman et al. 2012). As such we would generally consider these variants to be variants of uncertain significance, probably benign. It is worth noting that amino acid 27514 is a poorly-conserved residue within the protein, and that 2 vertebrate species have methionine as the typical amino acid at this site. |