ClinVar Miner

Submissions for variant NM_001018005.2(TPM1):c.64G>A (p.Ala22Thr) (rs397516382)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000036351 SCV000060003 uncertain significance not specified 2018-03-06 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The p.Ala22Thr variant in TPM1 has been reported in 4 individuals with clinical features of HCM and segregated with disease in one affected relative (Otsuka 2012, Walsh 2016, Schymanski 2017). This variant has also been reported in ClinVar (Variation ID 4 3432) and has been identified in 1/14848 African chromosomes by the Genome Aggre gation Database (gnomAD,; dbSNP rs397516382). A lanine (Ala) at position 22 is highly conserved in mammals and across evolutiona rily distant species, and the change to threonine (Thr) was predicted to be path ogenic using a computational tool clinically validated by our laboratory. This t ool's pathogenic prediction is estimated to be correct 94% of the time (Jordan 2 011). In summary, while there is some suspicion for a pathogenic role, the clini cal significance of the p.Ala22Thr variant is uncertain. ACMG/AMP Criteria appli ed: PM2; PP3; PS4_Supporting.
GeneDx RCV000223842 SCV000209345 uncertain significance not provided 2017-03-03 criteria provided, single submitter clinical testing The A22T variant of uncertain significance in the TPM1 gene has been reported in association withHCM (Otsuka et al., 2012; Coppini et al., 2014). Otsuka et al., (2012) identified the A22T variant ina mother and son with HCM; it was absent from 400 ethnically-matched control alleles. Subsequently,Coppini et al. (2014) reported A22T as a likely pathogenic variant in one additional individual withHCM. This variant has been identified independently and/or in conjunction with additionalcardiogenetic variants in individuals referred for HCM genetic testing at GeneDx. So far, segregationdata is limited or absent for these individuals due to the lack of clinical information provided and/orinsufficient participation by informative family members. Two other clinical laboratories classifyA22T as a variant of uncertain significance in ClinVar (SCV000060003.4; SCV000220105.1; Landrumet al., 2016), one of which also published their classification in a separate study (Alfares et al., 2015).The A22T variant was not observed in approximately 6,500 individuals of European and AfricanAmerican ancestry in the NHLBI Exome Sequencing Project or in the 1000 Genomes Project,indicating it is not a common benign variant in these populations.The A22T variant results in a non-conservative amino substitution of a Threonine at a residue that isconserved across species. Consequently, in silico analysis predicts A22T is probably damaging to theprotein structure/function.Therefore, based on the currently available information, it is unclear whether this variant is apathogenic variant or a rare benign variant.
Ambry Genetics RCV000618601 SCV000740196 uncertain significance Cardiovascular phenotype 2018-07-09 criteria provided, single submitter clinical testing Insufficient evidence
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV001170562 SCV001333148 uncertain significance Cardiomyopathy 2018-02-13 criteria provided, single submitter clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000223842 SCV000280540 likely pathogenic not provided 2014-07-16 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.Ala22Thr (c.64 G>A) in TPM1. Given case data and absence in ancestry- matched controls we consider this variant likely disease causing. The variant has been seen in at least 4 unrelated cases of HCM (not including this patient's family). There is weak segregation data in one family. Otsuko et al (2011) observed the variant in one patient from their cohort of 112 unrelated Japanese patients with HCM. The variant segregated with disease in two affected first degree relatives. The variant is listed in ClinVar, with data submitted by LMM (SCV000060003). They note that they have observed the variant in two Black patients with HCM. They classify it as a variant of uncertain significance and last reviewed it in December 2012. We have seen the variant in one other patient in our center, a patient with HCM of mixed ancestry (Korean, Black, Native American, Mongolian). In silico analysis with PolyPhen-2 predicts the variant to be probably damaging. The alanine at codon 22 is conserved across species, as are neighboring amino acids. I could not find any other variants reported in association with disease at this codon, however there are variants reported in association with disease at nearby codons: p.Arg21His (Fokstuen et al 2011), p.Glu23Gln (Hershberger et al 2010), p.Asp28Asn (Bos et al 2013). In total the variant has not been seen in ~7100 laboratory controls, published controls and individuals from publicly available population datasets. There is no variation at codon 22 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6500 Caucasian and African American individuals (as of June 16th, 2014). The ClinVar entry from LMM notes that coverage was insufficient in ESP to assess this variant’s presence. The variant is listed in dbSNP, pointing to the LMM data (as of June 9th, 2014). The variant was not observed in the following laboratory and published control samples: 200 Japanese individuals who were presumed healthy (Otsuko et al 2011).

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