ClinVar Genomic variation as it relates to human health
NM_017636.4(TRPM4):c.1575G>A (p.Trp525Ter)
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.
Uncertain significance(1); Benign(3); Likely benign(3)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_017636.4(TRPM4):c.1575G>A (p.Trp525Ter)
Variation ID: 241176 Accession: VCV000241176.68
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19q13.33 19: 49686146 (GRCh37) [ NCBI UCSC ] 19: 49182889 (GRCh38) [ 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 Oct 23, 2016 May 1, 2024 Jan 26, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_017636.4:c.1575G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_060106.2:p.Trp525Ter nonsense NM_001195227.2:c.1575G>A NP_001182156.1:p.Trp525Ter nonsense NM_001321281.2:c.1230G>A NP_001308210.1:p.Trp410Ter nonsense NM_001321282.2:c.-1+22G>A intron variant NM_001321283.2:c.1053G>A NP_001308212.1:p.Trp351Ter nonsense NM_001321285.2:c.513G>A NP_001308214.1:p.Trp171Ter nonsense NC_000019.10:g.49182889G>A NC_000019.9:g.49686146G>A NG_027551.2:g.30131G>A - Protein change
- W525*, W171*, W351*, W410*
- Other names
- -
- Canonical SPDI
- NC_000019.10:49182888: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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0.00040 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 0.00040
1000 Genomes Project 30x 0.00047
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00075
Trans-Omics for Precision Medicine (TOPMed) 0.00105
The Genome Aggregation Database (gnomAD), exomes 0.00149
Exome Aggregation Consortium (ExAC) 0.00157
The Genome Aggregation Database (gnomAD) 0.00168
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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TRPM4 | - | - |
GRCh38 GRCh37 |
1660 | 1680 |
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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Benign/Likely benign (3) |
criteria provided, multiple submitters, no conflicts
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Jan 26, 2024 | RCV000227821.30 | |
Uncertain significance (1) |
criteria provided, single submitter
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Dec 4, 2023 | RCV000256482.10 | |
Benign (2) |
criteria provided, multiple submitters, no conflicts
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Feb 17, 2023 | RCV000426179.10 | |
Likely benign (4) |
criteria provided, single submitter
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Aug 10, 2020 | RCV001529188.18 | |
Likely benign (1) |
criteria provided, single submitter
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Apr 3, 2019 | RCV002392715.9 |
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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Benign
(Jan 26, 2024)
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criteria provided, single submitter
Method: clinical testing
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Progressive familial heart block type IB
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000290319.10
First in ClinVar: Jul 01, 2016 Last updated: Feb 20, 2024 |
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Benign
(Oct 27, 2016)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000527971.4
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
Comment:
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at … (more)
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. (less)
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Uncertain significance
(Dec 04, 2023)
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criteria provided, single submitter
Method: research
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Sudden cardiac death
Affected status: yes
Allele origin:
germline
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Scripps Translational Science Institute, Scripps Health and The Scripps Research Institute
Study: Molecular Autopsy
Accession: SCV000323205.2 First in ClinVar: Oct 23, 2016 Last updated: Dec 09, 2023 |
Number of individuals with the variant: 4
Family history: yes
Comment on evidence:
Sudden cardiac death in a 29 year old male, episodes of heart palpatiations 2 weeks prior to death. Mother (60 years old) and sister (37 … (more)
Sudden cardiac death in a 29 year old male, episodes of heart palpatiations 2 weeks prior to death. Mother (60 years old) and sister (37 years old) appear to be asymptomatic carriers. Another sister (38 years old) and carrier of the mutation has had heart palpitations and has been monitored with a Holter study. Brother (35 years old) is also a carrier of the mutation and has had episodes of bradychardia. (less)
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Likely benign
(Apr 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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Progressive familial heart block type IB
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001295711.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
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Likely benign
(Aug 10, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV001472840.1
First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021 |
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Benign
(Feb 17, 2023)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV003844936.1
First in ClinVar: Mar 26, 2023 Last updated: Mar 26, 2023 |
Comment:
Variant summary: TRPM4 c.1575G>A (p.Trp525X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: TRPM4 c.1575G>A (p.Trp525X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay. It is not possible to predict the impact of this nonsense variant since Gain-of-Function is the common mechanism of disease for TRPM4 in Progressive Familial Heart Block, Type 1B (OMIM 606936). The variant allele was found at a frequency of 0.0015 in 260054 control chromosomes in the gnomAD database, including 3 homozygotes. The observed variant frequency is approximately 600 fold of the estimated maximal expected allele frequency for a pathogenic variant in TRPM4 causing Progressive Familial Heart Block Type 1B phenotype (2.5e-06), strongly suggesting that the variant is benign. Seven ClinVar submitters have assessed the variant since 2014: one classified the variant as uncertain significance, one as likely pathogenic, three as likely benign, and two as benign. Based on the evidence outlined above, the variant was classified as benign. (less)
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Likely benign
(Apr 03, 2019)
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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: SCV002703342.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more)
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
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Likely benign
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001742232.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021 |
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Likely benign
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001924058.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
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Likely benign
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001970053.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
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Uncertain significance
(Aug 28, 2019)
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Flagged submission
flagged submission
Method: clinical testing
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
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Progressive familial heart block type IB
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002557595.1
First in ClinVar: Aug 08, 2022 Last updated: Aug 08, 2022 |
Comment:
A heterozygous nonsense variant was identified, NM_017636.3(TRPM4):c.1575G>A in exon 11 of 25 of the TRPM4 gene. (NB: This variant is non-coding in alternative transcript NM_001321282.1). … (more)
A heterozygous nonsense variant was identified, NM_017636.3(TRPM4):c.1575G>A in exon 11 of 25 of the TRPM4 gene. (NB: This variant is non-coding in alternative transcript NM_001321282.1). This nonsense variant is predicted to create a change of tryptophan to a stop at amino acid position 525 of the protein, NP_060106.2(TRPM4):p.(Trp525*), resulting in the loss of normal protein function through nonsense-mediated decay (NMD). The variant is present in the gnomAD population database at a frequency of 0.15% (380 heterozygotes, 3 homozygotes). It has been previously reported in patients with SIDS and Brugada syndrome (Janin, A., et al. (2019), Neubauer, J., et al. (2017), Hertz, C. L., et al. (2016)), but also reported as both benign, likely benign and likely pathogenic (LOVD, ClinVar). Other variants predicted to cause NMD have been reported as both a VUS and likely benign (ClinVar). Based on information available at the time of curation, this variant has been classified as a VARIANT of UNCERTAIN SIGNIFICANCE (VUS). (less)
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Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more |
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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TRPM4 mutations to cause autosomal recessive and not autosomal dominant Brugada type 1 syndrome. | Janin A | European journal of medical genetics | 2019 | PMID: 30142439 |
Post-mortem whole-exome analysis in a large sudden infant death syndrome cohort with a focus on cardiovascular and metabolic genetic diseases. | Neubauer J | European journal of human genetics : EJHG | 2017 | PMID: 28074886 |
Genetic investigations of sudden unexpected deaths in infancy using next-generation sequencing of 100 genes associated with cardiac diseases. | Hertz CL | European journal of human genetics : EJHG | 2016 | PMID: 26350513 |
Association transient receptor potential melastatin channel gene polymorphism with primary open angle glaucoma. | Okumus S | Molecular vision | 2013 | PMID: 24019741 |
Text-mined citations for rs71352737 ...
HelpRecord last updated May 01, 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.