VCV000448711.42 - ClinVar

NM_021625.5(TRPV4):c.523A>G (p.Thr175Ala)

Germline

Classification

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.

(12)

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
Uncertain significance(10); Likely benign(2)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_021625.5(TRPV4):c.523A>G (p.Thr175Ala)

Variation ID: 448711 Accession: VCV000448711.42

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 12q24.11 12: 109808332 (GRCh38) [ NCBI UCSC ] 12: 110246137 (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	Dec 19, 2017	Oct 20, 2024	Oct 26, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_021625.5:c.523A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_067638.3:p.Thr175Ala	missense
NM_001177428.1:c.523A>G	NP_001170899.1:p.Thr175Ala	missense
NM_001177431.1:c.421A>G	NP_001170902.1:p.Thr141Ala	missense
NM_001177433.1:c.523A>G	NP_001170904.1:p.Thr175Ala	missense
NM_147204.2:c.523A>G	NP_671737.1:p.Thr175Ala	missense
NC_000012.12:g.109808332T>C
NC_000012.11:g.110246137T>C
NG_017090.1:g.30076A>G
LRG_372:g.30076A>G
LRG_372t1:c.523A>G	LRG_372p1:p.Thr175Ala

... more HGVS ... less HGVS

Protein change

T175A, T141A

Other names

Canonical SPDI

NC_000012.12:109808331:T:C

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD) 0.00002

Exome Aggregation Consortium (ExAC) 0.00003

The Genome Aggregation Database (gnomAD), exomes 0.00003

Trans-Omics for Precision Medicine (TOPMed) 0.00003

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008

Links

ClinGen: CA6780524 dbSNP: rs146304351 VarSome

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
Gene	OMIM	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.
TRPV4		-	-	GRCh38 GRCh37	1138	1153

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.
not provided	Conflicting interpretations of pathogenicity (3)	criteria provided, conflicting classifications	Mar 30, 2022	RCV000994976.32
Brachyrachia (short spine dysplasia)	Uncertain significance (1)	criteria provided, single submitter	Apr 27, 2017	RCV001112861.11
Scapuloperoneal spinal muscular atrophy	Uncertain significance (1)	criteria provided, single submitter	Apr 27, 2017	RCV001114213.11
Neuronopathy, distal hereditary motor, autosomal dominant 8	Uncertain significance (1)	criteria provided, single submitter	Apr 27, 2017	RCV001114215.11
Charcot-Marie-Tooth disease axonal type 2C	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Oct 26, 2023	RCV000684901.19
Metatropic dysplasia	Uncertain significance (1)	criteria provided, single submitter	Apr 27, 2017	RCV001114214.11
Spondylometaphyseal dysplasia, Kozlowski type	Likely benign (1)	criteria provided, single submitter	Apr 27, 2017	RCV001114216.11
Charcot-Marie-Tooth disease	Uncertain significance (1)	criteria provided, single submitter	-	RCV001173247.8
Inborn genetic diseases	Uncertain significance (1)	criteria provided, single submitter	Feb 26, 2020	RCV002341214.9

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.
Uncertain significance (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Brachyrachia (short spine dysplasia) Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001270565.1 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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
Uncertain significance (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Charcot-Marie-Tooth disease axonal type 2C Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001272066.1 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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
Uncertain significance (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Neuronopathy, distal hereditary motor, autosomal dominant 8 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001272067.1 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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
Uncertain significance (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Scapuloperoneal spinal muscular atrophy Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001272064.1 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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
Uncertain significance (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Metatropic dysplasia Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001272065.1 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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
Likely benign (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Spondylometaphyseal dysplasia, Kozlowski type Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001272068.1 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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
Uncertain significance (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Charcot-Marie-Tooth disease Affected status: yes Allele origin: germline	Molecular Genetics Laboratory, London Health Sciences Centre Accession: SCV001336330.1 First in ClinVar: Jun 14, 2020 Last updated: Jun 14, 2020
Uncertain significance (Mar 30, 2022)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Athena Diagnostics Accession: SCV000615860.2 First in ClinVar: Dec 19, 2017 Last updated: Dec 31, 2022	Publications: PubMed (1) PubMed: 19661060
Likely benign (Dec 04, 2019)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV002504565.2 First in ClinVar: Apr 29, 2022 Last updated: Mar 04, 2023	Comment: See Variant Classification Assertion Criteria.
Uncertain significance (Oct 26, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Charcot-Marie-Tooth disease axonal type 2C Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000812362.6 First in ClinVar: Oct 10, 2018 Last updated: Feb 20, 2024	Publications: PubMed (3) PubMed: 28492532‚ 32376792‚ 19661060 Comment: This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 175 of the TRPV4 protein (p.Thr175Ala). … (more) This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 175 of the TRPV4 protein (p.Thr175Ala). This variant is present in population databases (rs146304351, gnomAD 0.005%). This missense change has been observed in individual(s) with clinical features of Charcot-Marie-Tooth disease (PMID: 32376792). ClinVar contains an entry for this variant (Variation ID: 448711). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TRPV4 protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change affects TRPV4 function (PMID: 19661060). 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)
Uncertain significance (Feb 26, 2020)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002645362.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (1) PubMed: 19661060 Comment: The p.T175A variant (also known as c.523A>G), located in coding exon 2 of the TRPV4 gene, results from an A to G substitution at nucleotide … (more) The p.T175A variant (also known as c.523A>G), located in coding exon 2 of the TRPV4 gene, results from an A to G substitution at nucleotide position 523. The threonine at codon 175 is replaced by alanine, an amino acid with similar properties. Functional studies demonstrated that the p.T175A alteration reduced sensitization of cells to protein kinase C (PKC) activation but did not affect sensitization to cyclic AMP-dependent protein kinase (PKA) activation in an in vitro study (Fan HC et al. J. Biol. Chem., 2009 Oct;284:27884-91). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
Uncertain significance (Jun 01, 2019)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001148823.27 First in ClinVar: Feb 03, 2020 Last updated: Oct 20, 2024	Number of individuals with the variant: 1
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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, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

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, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Comment:

This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 175 of the TRPV4 protein (p.Thr175Ala). This variant is present in population databases (rs146304351, gnomAD 0.005%). This missense change has been observed in individual(s) with clinical features of Charcot-Marie-Tooth disease (PMID: 32376792). ClinVar contains an entry for this variant (Variation ID: 448711). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TRPV4 protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change affects TRPV4 function (PMID: 19661060). 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.T175A variant (also known as c.523A>G), located in coding exon 2 of the TRPV4 gene, results from an A to G substitution at nucleotide position 523. The threonine at codon 175 is replaced by alanine, an amino acid with similar properties. Functional studies demonstrated that the p.T175A alteration reduced sensitization of cells to protein kinase C (PKC) activation but did not affect sensitization to cyclic AMP-dependent protein kinase (PKA) activation in an in vitro study (Fan HC et al. J. Biol. Chem., 2009 Oct;284:27884-91). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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:

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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Comprehensive genetic sequence and copy number analysis for Charcot-Marie-Tooth disease in a Canadian cohort of 2517 patients.	Volodarsky M	Journal of medical genetics	2021	PMID: 32376792
Activation of the TRPV4 ion channel is enhanced by phosphorylation.	Fan HC	The Journal of biological chemistry	2009	PMID: 19661060

Text-mined citations for rs146304351 ...

These 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 19, 2024

ClinVar Genomic variation as it relates to human health

NM_021625.5(TRPV4):c.523A>G (p.Thr175Ala)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs146304351 ...