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

gnomAD frequency: 0.00001  dbSNP: rs397516382

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham 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, http://gnomad.broadinstitute.org; 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	The c.64G>A (p.A22T) alteration is located in exon 1 (coding exon 1) of the TPM1 gene. This alteration results from a G to A substitution at nucleotide position 64, causing the alanine (A) at amino acid position 22 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170562	SCV001333148	uncertain significance	Cardiomyopathy	2018-02-13	criteria provided, single submitter	clinical testing
Invitae	RCV001213017	SCV001384630	uncertain significance	Hypertrophic cardiomyopathy	2024-01-10	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 22 of the TPM1 protein (p.Ala22Thr). This variant is present in population databases (rs397516382, gnomAD 0.007%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 22112859, 25524337, 27532257). ClinVar contains an entry for this variant (Variation ID: 43432). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
3billion	RCV001807760	SCV002058610	likely pathogenic	Hypertrophic cardiomyopathy 3	2022-01-18	criteria provided, single submitter	clinical testing	Same nucleotide change resulting in same amino acid change has been previously reported to be associated with TPM1 related disorder (PMID:22112859, PS1_P). The variant has been observed in multiple (>7) similarly affected unrelated individuals (PS4_M) In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.818, 3CNET: 0.854, PP3_P). A missense variant is a common mechanism associated with Cardiomyopathy (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000008, PM2_M). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.
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).