The Glu16Gln variant in the TPM1 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Glu16Gln results in a semi-conservative amino acid substitution of a negatively charged Glutamic acid with a neutral, polar Glutamine at a position that is conserved across species. In silico analysis predicts Glu16Gln is probably damaging to the protein structure/function. Mutations in nearby residues (Met8Arg, Lys15Asn, Ala22Thr) have been reported in association with cardiomyopathy, further supporting the functional importance of this region of the protein. Furthermore, the NHLBI ESP Exome Variant Server reports Glu16Gln was not observed in approximately 6,500 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. In summary, while Glu16Gln is a good candidate for a disease-causing mutation, with the clinical and molecular information available at this time we cannot unequivocally determine the clinical significance of this variant. The variant is found in HCM panel(s).
ClinVar Genomic variation as it relates to human health
NM_001018005.2(TPM1):c.46G>C (p.Glu16Gln)
Germline
Classification
Help
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.
(5)
Help
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.
Conflicting classifications of pathogenicity
Likely pathogenic(2); Uncertain significance(3)
Likely pathogenic(2); Uncertain significance(3)
5
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001018005.2(TPM1):c.46G>C (p.Glu16Gln)
Variation ID: 177702 Accession: VCV000177702.13
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 15q22.2 15: 63042875 (GRCh38) [ NCBI UCSC ] 15: 63335074 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Feb 24, 2015 Apr 20, 2024 Jun 20, 2022 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001018005.2:c.46G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001018005.1:p.Glu16Gln missense NM_000366.6:c.46G>C NP_000357.3:p.Glu16Gln missense NM_001018004.2:c.46G>C NP_001018004.1:p.Glu16Gln missense NM_001018006.2:c.46G>C NP_001018006.1:p.Glu16Gln missense NM_001018007.2:c.46G>C NP_001018007.1:p.Glu16Gln missense NM_001018020.2:c.46G>C NP_001018020.1:p.Glu16Gln missense NM_001301244.2:c.46G>C NP_001288173.1:p.Glu16Gln missense NM_001365776.1:c.46G>C NP_001352705.1:p.Glu16Gln missense NM_001365777.1:c.46G>C NP_001352706.1:p.Glu16Gln missense NM_001365778.1:c.46G>C NP_001352707.1:p.Glu16Gln missense NM_001365779.1:c.46G>C NP_001352708.1:p.Glu16Gln missense NM_001407322.1:c.46G>C NP_001394251.1:p.Glu16Gln missense NM_001407323.1:c.46G>C NP_001394252.1:p.Glu16Gln missense NM_001407324.1:c.46G>C NP_001394253.1:p.Glu16Gln missense NM_001407325.1:c.46G>C NP_001394254.1:p.Glu16Gln missense NM_001407326.1:c.46G>C NP_001394255.1:p.Glu16Gln missense NM_001407327.1:c.46G>C NP_001394256.1:p.Glu16Gln missense NM_001407328.1:c.46G>C NP_001394257.1:p.Glu16Gln missense NM_001407329.1:c.46G>C NP_001394258.1:p.Glu16Gln missense NM_001407330.1:c.46G>C NP_001394259.1:p.Glu16Gln missense NM_001407331.1:c.46G>C NP_001394260.1:p.Glu16Gln missense NM_001407332.1:c.46G>C NP_001394261.1:p.Glu16Gln missense NM_001407333.1:c.46G>C NP_001394262.1:p.Glu16Gln missense NM_001407334.1:c.46G>C NP_001394263.1:p.Glu16Gln missense NM_001407335.1:c.46G>C NP_001394264.1:p.Glu16Gln missense NM_001407336.1:c.46G>C NP_001394265.1:p.Glu16Gln missense NM_001407337.1:c.46G>C NP_001394266.1:p.Glu16Gln missense NM_001407338.1:c.46G>C NP_001394267.1:p.Glu16Gln missense NR_176337.1:n.129G>C non-coding transcript variant NR_176338.1:n.129G>C non-coding transcript variant NR_176339.1:n.129G>C non-coding transcript variant NR_176340.1:n.129G>C non-coding transcript variant NR_176341.1:n.129G>C non-coding transcript variant NR_176342.1:n.129G>C non-coding transcript variant NR_176343.1:n.129G>C non-coding transcript variant NR_176344.1:n.129G>C non-coding transcript variant NR_176345.1:n.129G>C non-coding transcript variant NR_176346.1:n.129G>C non-coding transcript variant NR_176347.1:n.129G>C non-coding transcript variant NC_000015.10:g.63042875G>C NC_000015.9:g.63335074G>C NG_007557.1:g.5237G>C LRG_387:g.5237G>C LRG_387t1:c.46G>C LRG_387p1:p.Glu16Gln - Protein change
- E16Q
- Other names
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p.E16Q:GAG>CAG
- Canonical SPDI
- NC_000015.10:63042874:G:C
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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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Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- Links
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 | ||
|---|---|---|---|---|---|---|
| HI score
Help
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. |
|||
| TPM1 | No evidence available | No evidence available |
GRCh38 GRCh37 |
855 | 903 | |
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. |
|---|---|---|---|---|
| Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
Jun 20, 2022 | RCV000154303.16 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Nov 7, 2012 | RCV000159395.9 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Jun 10, 2021 | RCV001170561.11 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Apr 15, 2021 | RCV001375511.9 |
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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Likely pathogenic
(Nov 07, 2012)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000209341.9
First in ClinVar: Feb 24, 2015 Last updated: Feb 24, 2015 |
Comment:
The Glu16Gln variant in the TPM1 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Glu16Gln results … (more)
The Glu16Gln variant in the TPM1 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Glu16Gln results in a semi-conservative amino acid substitution of a negatively charged Glutamic acid with a neutral, polar Glutamine at a position that is conserved across species. In silico analysis predicts Glu16Gln is probably damaging to the protein structure/function. Mutations in nearby residues (Met8Arg, Lys15Asn, Ala22Thr) have been reported in association with cardiomyopathy, further supporting the functional importance of this region of the protein. Furthermore, the NHLBI ESP Exome Variant Server reports Glu16Gln was not observed in approximately 6,500 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. In summary, while Glu16Gln is a good candidate for a disease-causing mutation, with the clinical and molecular information available at this time we cannot unequivocally determine the clinical significance of this variant. The variant is found in HCM panel(s). (less)
|
|
|
Uncertain significance
(Jun 25, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Hypertrophic cardiomyopathy
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001376520.1
First in ClinVar: Jul 16, 2020 Last updated: Jul 16, 2020 |
Comment:
This sequence change replaces glutamic acid with glutamine at codon 16 of the TPM1 protein (p.Glu16Gln). The glutamic acid residue is weakly conserved and there … (more)
This sequence change replaces glutamic acid with glutamine at codon 16 of the TPM1 protein (p.Glu16Gln). The glutamic acid residue is weakly conserved and there is a small physicochemical difference between glutamic acid and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with hypertrophic cardiomyopathy (PMID: 28356264, 27532257). ClinVar contains an entry for this variant (Variation ID: 177702). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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
(Jun 10, 2021)
|
criteria provided, single submitter
Method: clinical testing
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Cardiomyopathy
Affected status: unknown
Allele origin:
germline
|
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV001333147.2
First in ClinVar: May 31, 2020 Last updated: Mar 11, 2023 |
|
|
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Uncertain Significance
(Jun 20, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hypertrophic cardiomyopathy
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000203963.5
First in ClinVar: Jan 31, 2015 Last updated: Apr 20, 2024 |
Comment:
The p.Glu16Gln variant in TPM1 has been reported in 2 individuals with hypertrophic cardiomyopathy (HCM), including as a denovo occurrence in 1 individual, though parental … (more)
The p.Glu16Gln variant in TPM1 has been reported in 2 individuals with hypertrophic cardiomyopathy (HCM), including as a denovo occurrence in 1 individual, though parental testing was not confirmed (Gomez 2017 PMID: 28356264, Walsh 2017 PMID: 27532257, LMM data). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 177702) and was absent from large population studies. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PS4_Supporting, PM6, PM2_Supporting, PP3. (less)
|
|
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Uncertain significance
(Apr 15, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001572361.1
First in ClinVar: Apr 30, 2021 Last updated: Apr 30, 2021 |
Comment:
Variant summary: TPM1 c.46G>C (p.Glu16Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging … (more)
Variant summary: TPM1 c.46G>C (p.Glu16Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 248708 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.46G>C has been reported in the literature in individuals affected with Hypertrophic Cardiomyopathy (e.g. Gomez_2014, Walsh_2017). These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One ClinVar submitter (evaluation after 2014) cites the variant as likely pathogenic while another ClinVar submitter (evaluation after 2014) cites it as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
|
Comment:
Comment:
This sequence change replaces glutamic acid with glutamine at codon 16 of the TPM1 protein (p.Glu16Gln). The glutamic acid residue is weakly conserved and there is a small physicochemical difference between glutamic acid and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with hypertrophic cardiomyopathy (PMID: 28356264, 27532257). ClinVar contains an entry for this variant (Variation ID: 177702). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
Comment:
The p.Glu16Gln variant in TPM1 has been reported in 2 individuals with hypertrophic cardiomyopathy (HCM), including as a denovo occurrence in 1 individual, though parental testing was not confirmed (Gomez 2017 PMID: 28356264, Walsh 2017 PMID: 27532257, LMM data). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 177702) and was absent from large population studies. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PS4_Supporting, PM6, PM2_Supporting, PP3.
Comment:
Variant summary: TPM1 c.46G>C (p.Glu16Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 248708 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.46G>C has been reported in the literature in individuals affected with Hypertrophic Cardiomyopathy (e.g. Gomez_2014, Walsh_2017). These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One ClinVar submitter (evaluation after 2014) cites the variant as likely pathogenic while another ClinVar submitter (evaluation after 2014) cites it as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
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. |
Comment:
The Glu16Gln variant in the TPM1 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Glu16Gln results in a semi-conservative amino acid substitution of a negatively charged Glutamic acid with a neutral, polar Glutamine at a position that is conserved across species. In silico analysis predicts Glu16Gln is probably damaging to the protein structure/function. Mutations in nearby residues (Met8Arg, Lys15Asn, Ala22Thr) have been reported in association with cardiomyopathy, further supporting the functional importance of this region of the protein. Furthermore, the NHLBI ESP Exome Variant Server reports Glu16Gln was not observed in approximately 6,500 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. In summary, while Glu16Gln is a good candidate for a disease-causing mutation, with the clinical and molecular information available at this time we cannot unequivocally determine the clinical significance of this variant. The variant is found in HCM panel(s).
Comment:
This sequence change replaces glutamic acid with glutamine at codon 16 of the TPM1 protein (p.Glu16Gln). The glutamic acid residue is weakly conserved and there is a small physicochemical difference between glutamic acid and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with hypertrophic cardiomyopathy (PMID: 28356264, 27532257). ClinVar contains an entry for this variant (Variation ID: 177702). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
Comment:
The p.Glu16Gln variant in TPM1 has been reported in 2 individuals with hypertrophic cardiomyopathy (HCM), including as a denovo occurrence in 1 individual, though parental testing was not confirmed (Gomez 2017 PMID: 28356264, Walsh 2017 PMID: 27532257, LMM data). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 177702) and was absent from large population studies. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PS4_Supporting, PM6, PM2_Supporting, PP3.
Comment:
Variant summary: TPM1 c.46G>C (p.Glu16Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 248708 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.46G>C has been reported in the literature in individuals affected with Hypertrophic Cardiomyopathy (e.g. Gomez_2014, Walsh_2017). These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One ClinVar submitter (evaluation after 2014) cites the variant as likely pathogenic while another ClinVar submitter (evaluation after 2014) cites it as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Screening of the Filamin C Gene in a Large Cohort of Hypertrophic Cardiomyopathy Patients. | Gómez J | Circulation. Cardiovascular genetics | 2017 | PMID: 28356264 |
| 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 |
| Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. | Richards S | Genetics in medicine : official journal of the American College of Medical Genetics | 2015 | PMID: 25741868 |
| Mutation analysis of the main hypertrophic cardiomyopathy genes using multiplex amplification and semiconductor next-generation sequencing. | Gómez J | Circulation journal : official journal of the Japanese Circulation Society | 2014 | PMID: 25342278 |
Text-mined citations for rs727504290 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Nov 10, 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.