ClinVar Genomic variation as it relates to human health
NM_001018005.2(TPM1):c.64G>A (p.Ala22Thr)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Likely pathogenic(1); Uncertain significance(5)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001018005.2(TPM1):c.64G>A (p.Ala22Thr)
Variation ID: 43432 Accession: VCV000043432.18
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 15q22.2 15: 63042893 (GRCh38) [ NCBI UCSC ] 15: 63335092 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Jun 3, 2016 Feb 14, 2024 Jan 10, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001018005.2:c.64G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001018005.1:p.Ala22Thr missense NM_000366.6:c.64G>A NP_000357.3:p.Ala22Thr missense NM_001018004.2:c.64G>A NP_001018004.1:p.Ala22Thr missense NM_001018006.2:c.64G>A NP_001018006.1:p.Ala22Thr missense NM_001018007.2:c.64G>A NP_001018007.1:p.Ala22Thr missense NM_001018020.2:c.64G>A NP_001018020.1:p.Ala22Thr missense NM_001301244.2:c.64G>A NP_001288173.1:p.Ala22Thr missense NM_001365776.1:c.64G>A NP_001352705.1:p.Ala22Thr missense NM_001365777.1:c.64G>A NP_001352706.1:p.Ala22Thr missense NM_001365778.1:c.64G>A NP_001352707.1:p.Ala22Thr missense NM_001365779.1:c.64G>A NP_001352708.1:p.Ala22Thr missense NC_000015.10:g.63042893G>A NC_000015.9:g.63335092G>A NG_007557.1:g.5255G>A LRG_387:g.5255G>A LRG_387t1:c.64G>A LRG_387p1:p.Ala22Thr - Protein change
- A22T
- Other names
- p.A22T:GCT>ACT
- Canonical SPDI
- NC_000015.10:63042892:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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0.00020 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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TPM1 | No evidence available | No evidence available |
GRCh38 GRCh37 |
797 | - |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Uncertain significance (1) |
criteria provided, single submitter
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Mar 6, 2018 | RCV000036351.11 | |
Uncertain significance (2) |
criteria provided, single submitter
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Mar 3, 2017 | RCV000223842.2 | |
Uncertain significance (1) |
criteria provided, single submitter
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May 25, 2023 | RCV000618601.3 | |
Uncertain significance (1) |
criteria provided, single submitter
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Feb 13, 2018 | RCV001170562.2 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 10, 2024 | RCV001213017.5 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jan 18, 2022 | RCV001807760.1 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Uncertain significance
(Mar 06, 2018)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000060003.6
First in ClinVar: May 03, 2013 Last updated: Aug 26, 2019 |
Comment:
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 … (more)
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. (less)
Number of individuals with the variant: 3
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Uncertain significance
(Feb 13, 2018)
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criteria provided, single submitter
Method: clinical testing
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Cardiomyopathy
Affected status: unknown
Allele origin:
germline
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CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV001333148.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
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Uncertain significance
(May 25, 2023)
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criteria provided, single submitter
Method: clinical testing
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Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000740196.5
First in ClinVar: Apr 14, 2018 Last updated: Jul 08, 2023 |
Comment:
The p.A22T variant (also known as c.64G>A), located in coding exon 1 of the TPM1 gene, results from a G to A substitution at nucleotide … (more)
The p.A22T variant (also known as c.64G>A), located in coding exon 1 of the TPM1 gene, results from a G to A substitution at nucleotide position 64. The alanine at codon 22 is replaced by threonine, an amino acid with similar properties. This alteration has been reported in several hypertrophic cardiomyopathy (HCM) cohorts and segregated with disease in one relative; however, clinical details were limited in some cases (Otsuka H et al. Circ. J. 2012;76:453-61; Coppini R et al. J. Am. Coll. Cardiol. 2014;64:2589-600; Alfares AA et al. Genet. Med. 2015;17:880-8). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
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Uncertain significance
(Mar 03, 2017)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000209345.11
First in ClinVar: Feb 24, 2015 Last updated: Apr 17, 2019 |
Comment:
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 … (more)
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. (less)
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Likely pathogenic
(Jan 18, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy 3
Affected status: yes
Allele origin:
germline
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3billion
Accession: SCV002058610.2
First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022 |
Comment:
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 … (more)
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. (less)
Clinical Features:
Left ventricular hypertrophy (present)
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Uncertain significance
(Jan 10, 2024)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001384630.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
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). … (more)
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. (less)
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Likely pathogenic
(Jul 16, 2014)
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no assertion criteria provided
Method: clinical testing
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Not provided
Affected status: not provided
Allele origin:
germline
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Stanford Center for Inherited Cardiovascular Disease, Stanford University
Accession: SCV000280540.1
First in ClinVar: Jun 03, 2016 Last updated: Jun 03, 2016 |
Comment:
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 … (more)
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). (less)
Number of individuals with the variant: 2
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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The genetic architecture of pediatric cardiomyopathy. | Ware SM | American journal of human genetics | 2022 | PMID: 35026164 |
Impact of variant reclassification in the clinical setting of cardiovascular genetics. | VanDyke RE | Journal of genetic counseling | 2021 | PMID: 33029862 |
Clinical laboratories collaborate to resolve differences in variant interpretations submitted to ClinVar. | Harrison SM | Genetics in medicine : official journal of the American College of Medical Genetics | 2017 | PMID: 28301460 |
Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples. | Walsh R | Genetics in medicine : official journal of the American College of Medical Genetics | 2017 | PMID: 27532257 |
Results of clinical genetic testing of 2,912 probands with hypertrophic cardiomyopathy: expanded panels offer limited additional sensitivity. | Alfares AA | Genetics in medicine : official journal of the American College of Medical Genetics | 2015 | PMID: 25611685 |
Clinical phenotype and outcome of hypertrophic cardiomyopathy associated with thin-filament gene mutations. | Coppini R | Journal of the American College of Cardiology | 2014 | PMID: 25524337 |
Prevalence and distribution of sarcomeric gene mutations in Japanese patients with familial hypertrophic cardiomyopathy. | Otsuka H | Circulation journal : official journal of the Japanese Circulation Society | 2012 | PMID: 22112859 |
Text-mined citations for rs397516382 ...
HelpRecord last updated Feb 20, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.