VCV000575960.13 - ClinVar

NM_021625.5(TRPV4):c.184G>A (p.Asp62Asn)

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.

(6)

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

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_021625.5(TRPV4):c.184G>A (p.Asp62Asn)

Variation ID: 575960 Accession: VCV000575960.13

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 12q24.11 12: 110252418 (GRCh37) [ NCBI UCSC ] 12: 109814613 (GRCh38) [ 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	Oct 10, 2018	Oct 26, 2024	Oct 15, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_021625.5:c.184G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_067638.3:p.Asp62Asn	missense
NM_001177428.1:c.184G>A	NP_001170899.1:p.Asp62Asn	missense
NM_001177431.1:c.82G>A	NP_001170902.1:p.Asp28Asn	missense
NM_001177433.1:c.184G>A	NP_001170904.1:p.Asp62Asn	missense
NM_147204.2:c.184G>A	NP_671737.1:p.Asp62Asn	missense
NC_000012.12:g.109814613C>T
NC_000012.11:g.110252418C>T
NG_017090.1:g.23795G>A
LRG_372:g.23795G>A
LRG_372t1:c.184G>A	LRG_372p1:p.Asp62Asn

... more HGVS ... less HGVS

Protein change

D62N, D28N

Other names

Canonical SPDI

NC_000012.12:109814612:C:T

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.

Trans-Omics for Precision Medicine (TOPMed) 0.00000

Exome Aggregation Consortium (ExAC) 0.00001

The Genome Aggregation Database (gnomAD) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00001

Links

dbSNP: rs770149544 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	1137	1152

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.
Charcot-Marie-Tooth disease axonal type 2C	Uncertain significance (1)	criteria provided, single submitter	Oct 15, 2023	RCV000698320.7
Avascular necrosis of femoral head, primary, 2 Brachyrachia (short spine dysplasia) Charcot-Marie-Tooth disease axonal type 2C Familial digital arthropathy-brachydactyly Metatropic dysplasia Neuronopathy, distal hereditary motor, autosomal dominant 8 Parastremmatic dwarfism Scapuloperoneal spinal muscular atrophy Sodium serum level quantitative trait locus 1 Spondyloepimetaphyseal dysplasia, Maroteaux type Spondylometaphyseal dysplasia, Kozlowski type	Uncertain significance (1)	criteria provided, single submitter	Oct 31, 2018	RCV000765043.2
Distal spinal muscular atrophy	Uncertain significance (1)	no assertion criteria provided	Aug 14, 2019	RCV000856935.1
Charcot-Marie-Tooth disease	Uncertain significance (1)	criteria provided, single submitter	-	RCV001173256.1
Inborn genetic diseases	Uncertain significance (1)	criteria provided, single submitter	Apr 23, 2021	RCV002406606.2
Familial digital arthropathy-brachydactyly	Likely pathogenic (1)	no assertion criteria provided	Jun 1, 2022	RCV004768581.1

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.
Uncertain significance (Oct 31, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Brachyrachia (short spine dysplasia) Metatropic dysplasia Parastremmatic dwarfism Scapuloperoneal spinal muscular atrophy Spondyloepimetaphyseal dysplasia, Maroteaux type Spondylometaphyseal dysplasia, Kozlowski type Neuronopathy, distal hereditary motor, autosomal dominant 8 Charcot-Marie-Tooth disease axonal type 2C Familial digital arthropathy-brachydactyly Sodium serum level quantitative trait locus 1 Avascular necrosis of femoral head, primary, 2 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000896240.1 First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
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: SCV001336339.1 First in ClinVar: Jun 14, 2020 Last updated: Jun 14, 2020
Uncertain significance (Oct 15, 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: SCV000826980.4 First in ClinVar: Oct 10, 2018 Last updated: Feb 28, 2024	Publications: PubMed (2) PubMed: 28492532‚ 25900305 Comment: This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 62 of the TRPV4 protein … (more) This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 62 of the TRPV4 protein (p.Asp62Asn). This variant is present in population databases (rs770149544, gnomAD 0.003%). This missense change has been observed in individual(s) with TRPV4-related conditions (PMID: 25900305). ClinVar contains an entry for this variant (Variation ID: 575960). 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. 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 (Apr 23, 2021)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002715163.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (3) PubMed: 25900305‚ 26392352‚ 28251916 Comment: The p.D62N variant (also known as c.184G>A), located in coding exon 1 of the TRPV4 gene, results from a G to A substitution at nucleotide … (more) The p.D62N variant (also known as c.184G>A), located in coding exon 1 of the TRPV4 gene, results from a G to A substitution at nucleotide position 184. The aspartic acid at codon 62 is replaced by asparagine, an amino acid with highly similar properties. This variant was detected in an individual with Charcot-Marie-Tooth disease type 2C and her brother with bilateral talipes (Evangelista T et al. Neuromuscul Disord, 2015 Jun;25:516-21). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
Uncertain significance (Aug 14, 2019)	no assertion criteria provided Method: research	Distal spinal muscular atrophy Affected status: yes Allele origin: germline	Genesis Genome Database Accession: SCV000999499.1 First in ClinVar: Dec 06, 2019 Last updated: Dec 06, 2019
Likely pathogenic (Jun 01, 2022)	no assertion criteria provided Method: provider interpretation	Familial digital arthropathy-brachydactyly Affected status: yes Allele origin: inherited	Solve-RD Consortium Accession: SCV005091430.1 First in ClinVar: Oct 26, 2024 Last updated: Oct 26, 2024 Comment: Variant identified during reanalysis of unsolved cases by the Solve-RD project. The Solve-RD project has received funding from the European Union’s Horizon 2020 research and … (more) Variant identified during reanalysis of unsolved cases by the Solve-RD project. The Solve-RD project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 779257. (less)	Comment: Variant confirmed as disease-causing by referring clinical team

Comment:

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 62 of the TRPV4 protein (p.Asp62Asn). This variant is present in population databases (rs770149544, gnomAD 0.003%). This missense change has been observed in individual(s) with TRPV4-related conditions (PMID: 25900305). ClinVar contains an entry for this variant (Variation ID: 575960). 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. 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.D62N variant (also known as c.184G>A), located in coding exon 1 of the TRPV4 gene, results from a G to A substitution at nucleotide position 184. The aspartic acid at codon 62 is replaced by asparagine, an amino acid with highly similar properties. This variant was detected in an individual with Charcot-Marie-Tooth disease type 2C and her brother with bilateral talipes (Evangelista T et al. Neuromuscul Disord, 2015 Jun;25:516-21). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Genetic heterogeneity of motor neuropathies.	Bansagi B	Neurology	2017	PMID: 28251916
Application of targeted multi-gene panel testing for the diagnosis of inherited peripheral neuropathy provides a high diagnostic yield with unexpected phenotype-genotype variability.	Antoniadi T	BMC medical genetics	2015	PMID: 26392352
Phenotypic variability of TRPV4 related neuropathies.	Evangelista T	Neuromuscular disorders : NMD	2015	PMID: 25900305

Text-mined citations for rs770149544 ...

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 Oct 27, 2024

ClinVar Genomic variation as it relates to human health

NM_021625.5(TRPV4):c.184G>A (p.Asp62Asn)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs770149544 ...