ClinVar Genomic variation as it relates to human health
NM_017636.4(TRPM4):c.1744G>A (p.Gly582Ser)
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(5); Benign(1); 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.1744G>A (p.Gly582Ser)
Variation ID: 35486 Accession: VCV000035486.37
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19q13.33 19: 49188641 (GRCh38) [ NCBI UCSC ] 19: 49691898 (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 Mar 1, 2016 Sep 16, 2024 Jul 21, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_017636.4:c.1744G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_060106.2:p.Gly582Ser missense NM_001195227.2:c.1744G>A NP_001182156.1:p.Gly582Ser missense NM_001321281.2:c.1399G>A NP_001308210.1:p.Gly467Ser missense NM_001321282.2:c.136G>A NP_001308211.1:p.Gly46Ser missense NM_001321283.2:c.1222G>A NP_001308212.1:p.Gly408Ser missense NM_001321285.2:c.682G>A NP_001308214.1:p.Gly228Ser missense NC_000019.10:g.49188641G>A NC_000019.9:g.49691898G>A NG_027551.2:g.35883G>A Q8TD43:p.Gly582Ser - Protein change
- G582S, G228S, G46S, G408S, G467S
- Other names
- -
- Canonical SPDI
- NC_000019.10:49188640: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
The Genome Aggregation Database (gnomAD) 0.00043
1000 Genomes Project 30x 0.00047
The Genome Aggregation Database (gnomAD), exomes 0.00051
Exome Aggregation Consortium (ExAC) 0.00053
Trans-Omics for Precision Medicine (TOPMed) 0.00067
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00069
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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HRC | - | - |
GRCh38 GRCh37 |
49 | 69 | |
TRPM4 | - | - |
GRCh38 GRCh37 |
1703 | 1724 |
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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Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
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Jan 30, 2024 | RCV000029158.31 | |
Uncertain significance (1) |
criteria provided, single submitter
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May 21, 2015 | RCV000208117.9 | |
Conflicting interpretations of pathogenicity (5) |
criteria provided, conflicting classifications
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Mar 17, 2022 | RCV001090742.23 | |
Uncertain significance (1) |
criteria provided, single submitter
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May 28, 2019 | RCV000990241.9 | |
Benign (1) |
criteria provided, single submitter
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Dec 3, 2018 | RCV002399335.9 | |
Likely benign (1) |
criteria provided, single submitter
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Jul 21, 2024 | RCV004700278.1 |
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
(Nov 07, 2017)
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criteria provided, single submitter
Method: clinical testing
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Progressive familial heart block type IB
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Study: VKGL Data-share Consensus
Accession: SCV000745391.1 First in ClinVar: Feb 13, 2018 Last updated: Feb 13, 2018 |
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Uncertain significance
(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: SCV001295714.1
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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
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Uncertain significance
(Mar 17, 2022)
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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: SCV003799326.2
First in ClinVar: Feb 13, 2023 Last updated: Mar 04, 2023 |
Comment:
The p.Gly582Ser variant (rs172149856) has been previously reported in a cardiac conductive block patient who also carried the p.Ala432Thr variant but this variant has not … (more)
The p.Gly582Ser variant (rs172149856) has been previously reported in a cardiac conductive block patient who also carried the p.Ala432Thr variant but this variant has not been reported alone (Stallmeyer et al 2012). This variant is listed in the NHLBI GO Exome Sequencing Project with an overall population frequency of 0.07 percent and is listed in the Exome Aggregation Consortium Browser with an overall population frequency of 0.05 percent. The glycine at position 582 is moderately conserved (considering 15 species, Alamut v2.7.1) and computational analyses of the effects of the p.Gly582Ser variant on protein structure and function predict this variant to be benign (SIFT: tolerated, MutationTaster: polymorphism, PolyPhen-2: benign). Because the p.Gly582Ser variant has not been observed without the p.Ala432Thr variant there is not enough evidence to classify this variant with certainty. Pathogenic variants of TRPM4 are inherited in an autosomal dominant manner and are associated with progressive familial heart block, type IB (MIM: 604599). (less)
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Uncertain significance
(May 21, 2015)
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criteria provided, single submitter
Method: clinical testing
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Brugada syndrome
Affected status: yes
Allele origin:
germline
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Blueprint Genetics
Accession: SCV000264272.2
First in ClinVar: Mar 01, 2016 Last updated: Mar 01, 2016 |
Number of individuals with the variant: 1
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Uncertain significance
(May 28, 2019)
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criteria provided, single submitter
Method: clinical testing
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Progressive familial heart block, type 1A
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV001141119.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
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Likely benign
(Mar 31, 2020)
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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: SCV000521220.4
First in ClinVar: Mar 08, 2017 Last updated: Dec 19, 2017 |
Comment:
This variant is associated with the following publications: (PMID: 21887725, 22750058, 26350513, 23382873, 27884173, 27207958, 28341588, 26820365)
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Likely benign
(Jan 30, 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000290321.8
First in ClinVar: Jul 01, 2016 Last updated: Feb 28, 2024 |
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Benign
(Dec 03, 2018)
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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: SCV002711587.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation … (more)
This alteration is classified as 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
(Jul 21, 2024)
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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: SCV005203361.1
First in ClinVar: Sep 16, 2024 Last updated: Sep 16, 2024 |
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Pathogenic
(Jan 01, 2012)
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no assertion criteria provided
Method: literature only
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PROGRESSIVE FAMILIAL HEART BLOCK, TYPE IB
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000051803.3
First in ClinVar: Apr 04, 2013 Last updated: Feb 13, 2018 |
Comment on evidence:
For discussion of the 1744G-A transition (c.1744G-A, NM_017636.3) in the TRPM4 gene, resulting in a gly582-to-ser (G582S) substitution, that was found in compound heterozygous state … (more)
For discussion of the 1744G-A transition (c.1744G-A, NM_017636.3) in the TRPM4 gene, resulting in a gly582-to-ser (G582S) substitution, that was found in compound heterozygous state in a patient with first-degree atrioventricular conduction block and atypical right bundle branch block (PFHB1B; 604559) by Stallmeyer et al. (2012), see 606936.0002. (less)
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Uncertain significance
(-)
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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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Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Study: VKGL Data-share Consensus
Accession: SCV001800097.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021 |
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Uncertain significance
(-)
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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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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001958157.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Uncertain significance
(-)
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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: SCV001920025.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
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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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Variants of Transient Receptor Potential Melastatin Member 4 in Childhood Atrioventricular Block. | Syam N | Journal of the American Heart Association | 2016 | PMID: 27207958 |
Targeted resequencing identifies TRPM4 as a major gene predisposing to progressive familial heart block type I. | Daumy X | International journal of cardiology | 2016 | PMID: 26820365 |
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 |
Mutational spectrum in the Ca(2+)--activated cation channel gene TRPM4 in patients with cardiac conductance disturbances. | Stallmeyer B | Human mutation | 2012 | PMID: 21887725 |
Text-mined citations for rs172149856 ...
HelpRecord last updated Oct 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.