ClinVar Miner

Submissions for variant NM_001018005.2(TPM1):c.523G>A (p.Asp175Asn) (rs104894503)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000474684 SCV000059992 pathogenic Hypertrophic cardiomyopathy 2016-05-03 criteria provided, single submitter clinical testing The p.Asp175Asn variant in TPM1 has been reported in multiple individuals with H CM, segregated with disease in more than 15 families, and occurred de novo in at least 1 individual (Thierfelder 1994, Nakajima-Taniguchi 1995, Watkins 1995, Co viello 1997, Van Driest 2002, Hedman 2004, Sipola 2005, Poutanen 2006, Jaaskelai nen 2013). It was also absent from large population studies. Additionally, funct ional studies support a pathogenic role for this variant (Bottinelli 1998, Muthu chamy 1999, Mathur 2011, Bai 2011, Borovikov 2011, Wang 2011, Li 2012, Ly 2012, Rysev 2012). In summary, the p.Asp175Asn variant meets our criteria to be classi fied as pathogenic for HCM in an autosomal dominant manner based on segregation studies and functional evidence.
Blueprint Genetics RCV000036340 SCV000188839 pathogenic Primary familial hypertrophic cardiomyopathy 2015-11-04 criteria provided, single submitter clinical testing
GeneDx RCV000159366 SCV000209312 pathogenic not provided 2018-06-26 criteria provided, single submitter clinical testing The D175N pathogenic variant has been identified in many individuals with hypertrophic cardiomyopathy (HCM), and has been reported as a common founder mutation in Finland, accounting for up to 11% of all cases of HCM in that population (Thierfelder et al., 1994; Hedman et al., 2004; Jääskeläinen et al., 2013). Hedman et al. (2004) found that 3/34 (9%) individuals with D175N presented with documented sudden cardiac death (SCD) at young/middle age, and 14/21 study subjects had two or more clinical markers of SCD, indicating substantial risk for life-threatening arrhythmia episodes. Data from the 5 families studied showed that the D175N variant was segregating with the HCM phenotype (Hedman et al., 2014). The D175N variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The D175N variant resides in the putative calcium-dependent troponin-T binding domain and is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Moreover, several functional studies have shown the deleterious effects of D175N (Muthuchamy et al., 1999; Mathur et al., 2011; Ly et al., 2012; Sewanan et al., 2016), including an in vitro study performed by Bottinelli et al. (1998) that showed that D175N results in increased calcium sensitivity.
Invitae RCV000474684 SCV000547697 pathogenic Hypertrophic cardiomyopathy 2019-12-20 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 175 of the TPM1 protein (p.Asp175Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with hypertrophic cardiomyopathy (HCM) in many families, and is a common cause of HCM in Finland (PMID: 8205619, 9060904, 22462493, 25548289). In addition, it has been reported to occur de novo in one individual affected with HCM (PMID: 7729014). Experimental studies have shown that this missense change increases the thin filament Ca2+ sensitivity (PMID: 9245729, 10900175, 22155441). In addition, a transgenic mouse that expresses this variant only in heart presented both structural and functional perturbations that resemble the phenotype observed in affected individuals (PMID: 10400910). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000622165 SCV000740009 pathogenic Cardiovascular phenotype 2019-03-22 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Deficient protein function in appropriate functional assay(s);Other strong data supporting pathogenic classification
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000474684 SCV000747373 pathogenic Hypertrophic cardiomyopathy 2017-01-01 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV001170568 SCV001333156 pathogenic Cardiomyopathy 2018-07-18 criteria provided, single submitter clinical testing
Color RCV001170568 SCV001346437 pathogenic Cardiomyopathy 2019-10-10 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001197088 SCV001367724 pathogenic mitochondrial 2016-01-01 criteria provided, single submitter clinical testing This variant was classified as: Uncertain significance. The following ACMG criteria were applied in classifying this variant: PP3,PM2,PP2. This variant was detected in homozygous state.
OMIM RCV000013272 SCV000033519 pathogenic Familial hypertrophic cardiomyopathy 3 1995-05-01 no assertion criteria provided literature only
Leiden Muscular Dystrophy (TPM1) RCV000013272 SCV000045883 not provided Familial hypertrophic cardiomyopathy 3 2012-04-15 no assertion provided curation
Integrated Genetics/Laboratory Corporation of America RCV000036340 SCV000053302 pathogenic Primary familial hypertrophic cardiomyopathy 2015-04-03 no assertion criteria provided clinical testing

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