ClinVar Miner

Submissions for variant NM_001018005.2(TPM1):c.688G>A (p.Asp230Asn) (rs199476317)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Baylor Genetics RCV000850515 SCV000992719 pathogenic Familial hypertrophic cardiomyopathy 3; Dilated cardiomyopathy 1Y 2018-10-12 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000024580 SCV000340451 pathogenic not provided 2016-03-11 criteria provided, single submitter clinical testing
GeneDx RCV000024580 SCV000209327 pathogenic not provided 2018-09-27 criteria provided, single submitter clinical testing The D230N pathogenic variant in the TPM1 gene has been reported in association with DCM (Lakdawala et al., 2010; Pugh et al., 2014; Walsh et al., 2017). This variant was reported to segregate with DCM in multiple members from two large families (Lakdawala et al., 2010). The D230N variant is not observed in large population cohorts (Lek et al., 2016). The D230N variant results in a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. Additionally, the D230 residue is conserved across species. Furthermore, functional studies indicated that the D230N variant significantly impaired sarcomere function compared to wild-type TPM1 protein (Lakdawala et al., 2010; Memo et al., 2013).
Invitae RCV000695968 SCV000824509 pathogenic Hypertrophic cardiomyopathy 2018-10-01 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 230 of the TPM1 protein (p.Asp230Asn). The aspartic acid residue is moderately 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 observed to segregate with dilated cardiomyopathy in two families (PMID: 20117437) and was observed in several unrelated individuals with dilated cardiomyopathy (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 31884). Experimental studies have shown that this missense change significantly decreases contractility of sarcomeres (PMID: 25242052, 25548289, 23539503, 28603979, 28600229). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000036354 SCV000060006 pathogenic Primary dilated cardiomyopathy 2015-10-13 criteria provided, single submitter clinical testing The p.Asp230Asn variant in TPM1 has been identified in 2 Caucasian individuals w ith DCM and segregated with disease in 14 affected relatives (Lakdawala 2010, LM M unpublished data). This variant was absent from large population studies. In a ddition, in vitro studies supported that this variant impacts contractility (Lak dawala 2010). In summary, the p.Asp230Asn variant meets our criteria to be class ified as pathogenic (http://pcpgm.partners.org/LMM) based on segregation and abs ence in controls.
Leiden Muscular Dystrophy (TPM1) RCV000024580 SCV000045889 not provided not provided 2012-04-15 no assertion provided curation
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000024580 SCV000280541 pathogenic not provided 2014-11-07 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.Asp230Asn (c.688 G>A) in TPM1 The variant has been seen in at least 2 unrelated cases of familial DCM with strong segregation data (not including our patient's family). Lakdawala et al (2010) observed the variant in two Caucasian families with DCM. Ten affected members of one family and 6 affected members of there other family carried the variant. The authors report that 21 of 25 unaffected adult family members did not have the variant. The combined LOD score was 5.22. There was marked intrafamilial variability with some family members diagnosed in the first year of life and others diagnosed in mid-adulthood. The same group later reported on early phenotypes in DCM including individuals with p.Asp230Asn (Lakdawala et al 2012). Presumably these were the same families as their prior report. This is a non-conservative amino acid substitution. The aspartate at codon 230 is conserved across species. PolyPhen predicts the variant to be possibly damaging. Lakdawala et al (2010) assessed the impact of the variant using an in vitro reconstituted sarcomere complex. They found inhibited sarcomere function with reduced calcium sensitivity, maximum activation and calcium affinity. A nearby variant has been reported in association with DCM, p.Ala239Thr (Stenson et al 2009). In total the variants has not been seen in at least 7000 published controls and publicly available general population samples. Lakdawala et al (2010) did not observe the variant in >500 Caucasian individuals. There is no variation at codon 230 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6500 Caucasian and African American individuals (as of October 28th, 2012). The variant is not listed in 1000 genomes (as of October 28th, 2012). It is listed in dbSNP, pointing to an online database for TPM1 variants that cites Lakdawala et al (2010).

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