VCV000004994.44 - ClinVar

NM_021625.5(TRPV4):c.1781G>A (p.Arg594His)

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.

(16)

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.

Pathogenic/Likely pathogenic

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.1781G>A (p.Arg594His)

Variation ID: 4994 Accession: VCV000004994.44

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 12q24.11 12: 109792695 (GRCh38) [ NCBI UCSC ] 12: 110230500 (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 21, 2015	Oct 20, 2024	Dec 20, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_021625.5:c.1781G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_067638.3:p.Arg594His	missense
NM_001177428.1:c.1640G>A	NP_001170899.1:p.Arg547His	missense
NM_001177431.1:c.1679G>A	NP_001170902.1:p.Arg560His	missense
NM_001177433.1:c.1460G>A	NP_001170904.1:p.Arg487His	missense
NM_147204.2:c.1601G>A	NP_671737.1:p.Arg534His	missense
NC_000012.12:g.109792695C>T
NC_000012.11:g.110230500C>T
NG_017090.1:g.45713G>A
LRG_372:g.45713G>A
LRG_372t1:c.1781G>A
	Q9HBA0:p.Arg594His

... more HGVS ... less HGVS

Protein change

R534H, R487H, R547H, R560H

Other names

R594H

Canonical SPDI

NC_000012.12:109792694: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.

Links

ClinGen: CA117168 UniProtKB: Q9HBA0#VAR_062333 OMIM: 605427.0003 dbSNP: rs77975504 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.
Spondylometaphyseal dysplasia, Kozlowski type	Pathogenic (6)	criteria provided, multiple submitters, no conflicts	Sep 1, 2022	RCV000005282.18
Parastremmatic dwarfism	Pathogenic (1)	no assertion criteria provided	Oct 1, 2010	RCV000005283.13
Neuromuscular disease Skeletal dysplasia	not provided (1)	no classification provided	-	RCV000202560.10
not provided	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Nov 22, 2023	RCV000498625.32
Charcot-Marie-Tooth disease axonal type 2C	Pathogenic (1)	criteria provided, single submitter	Dec 20, 2023	RCV000691603.14
Metatropic dysplasia	Pathogenic (1)	no assertion criteria provided	Oct 1, 2010	RCV001618207.10
Neuronopathy, distal hereditary motor, autosomal dominant 8	Likely pathogenic (1)	criteria provided, single submitter	Jun 30, 2021	RCV002243623.9
Inborn genetic diseases	Pathogenic (1)	criteria provided, single submitter	Dec 7, 2022	RCV002512802.9

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.
Pathogenic (Nov 30, 2019)	criteria provided, single submitter (Blueprint Genetics Variant Classification Scheme) Method: clinical testing	Not provided Affected status: yes Allele origin: germline	Blueprint Genetics Accession: SCV001832465.1 First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 Comment: Patient analyzed with Comprehensive Skeletal Dysplasias and Disorders Panel
Pathogenic (Sep 01, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Spondylometaphyseal dysplasia, Kozlowski type Affected status: yes Allele origin: germline	3billion Accession: SCV002572718.1 First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022	Comment: The variant is not observed in the gnomAD v2.1.1 dataset. It is located in a mutational hot spot and/or well-established functional domain in which established … (more) The variant is not observed in the gnomAD v2.1.1 dataset. It is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.89; 3Cnet: 0.77). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000004994). Different missense changes at the same codon (p.Arg594Cys, p.Arg594Ser) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV001224354 , VCV001484191). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Disproportionate short stature (present) , Disproportionate short-trunk short stature (present) , Lumbar hyperlordosis (present) , Kyphoscoliosis (present)
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Spondylometaphyseal dysplasia, Kozlowski type Affected status: yes Allele origin: de novo	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India Accession: SCV003924403.1 First in ClinVar: May 20, 2023 Last updated: May 20, 2023	Publications: DOI: 10.1016/j.ajhg.2009.01.021 DOI: 10.1016/j.ajhg.2009.01.021
Pathogenic (May 27, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: unknown	Molecular Diagnostics Lab, Nemours Children's Health, Delaware Accession: SCV000590827.1 First in ClinVar: Aug 20, 2017 Last updated: Aug 20, 2017	Publications: PubMed (3) PubMed: 19232556‚ 20503319‚ 20577006 Age: 0-9 years Sex: male
Pathogenic (Aug 10, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Spondylometaphyseal dysplasia, Kozlowski type Affected status: yes Allele origin: unknown	Laboratory of Medical Genetics, National & Kapodistrian University of Athens Accession: SCV001976764.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021	Publications: PubMed (1) PubMed: 34008892 Comment: PM1, PM2, PP2, PP3, PP5
Pathogenic (Aug 02, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Spondylometaphyseal dysplasia, Kozlowski type Affected status: yes Allele origin: germline	Centogene AG - the Rare Disease Company Accession: SCV002059725.1 First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022
Likely pathogenic (Jun 30, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Spinal Muscular Atrophy Distal Congenital Nonprogressive Affected status: yes Allele origin: germline	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein Accession: SCV002512733.1 First in ClinVar: May 21, 2022 Last updated: May 21, 2022	Comment: ACMG classification criteria: PS3 supporting, PS4 strong, PM2 moderate, PP3 supporting Geographic origin: Brazil
Pathogenic (Dec 20, 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: SCV000819389.5 First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024	Publications: PubMed (6) PubMed: 28492532‚ 19232556‚ 20503319‚ 20577006‚ 21658220‚ 21573172 Comment: This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 594 of the TRPV4 protein (p.Arg594His). … (more) This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 594 of the TRPV4 protein (p.Arg594His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with spondylometaphyseal dysplasia, Kozlowski type as well as other related skeletal dysplasias (PMID: 19232556, 20503319, 20577006, 21658220). ClinVar contains an entry for this variant (Variation ID: 4994). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TRPV4 protein function. Experimental studies have shown that this missense change affects TRPV4 function (PMID: 19232556, 21573172). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Dec 07, 2022)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV003652594.2 First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024	Publications: PubMed (7) PubMed: 19232556‚ 20577006‚ 21658220‚ 26377240‚ 28687525‚ 29776788‚ 32381727 Comment: The c.1781G>A (p.R594H) alteration is located in exon 11 (coding exon 10) of the TRPV4 gene. This alteration results from a G to A substitution … (more) The c.1781G>A (p.R594H) alteration is located in exon 11 (coding exon 10) of the TRPV4 gene. This alteration results from a G to A substitution at nucleotide position 1781, causing the arginine (R) at amino acid position 594 to be replaced by a histidine (H). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been detected in multiple individuals with Kozlowski type spondylometaphyseal dysplasia and metatropic dysplasia, including some cases of reported de novo occurrence (Krakow, 2009; Dai, 2010; Andreucci, 2011; Zhang, 2015; Bieganski, 2017; Hsu, 2019). Another alteration at the same codon, c.1780C>A (p.R594S), has been described in an individual with metatropic dysplasia (Andreucci, 2011). This amino acid position is highly conserved in available vertebrate species. Functional analysis demonstrated that the p.R594H alteration altered basal calcium channel activity in vitro (Krakow, 2009). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. (less)
Pathogenic (Nov 22, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV005202130.1 First in ClinVar: Sep 16, 2024 Last updated: Sep 16, 2024	Comment: Published functional studies demonstrate that R594H leads to increased constitutive and agonist-responsive activity, and R594 transgenic mice exhibited severe skeletal abnormalities (PMID: 19232556, 24644033); In … (more) Published functional studies demonstrate that R594H leads to increased constitutive and agonist-responsive activity, and R594 transgenic mice exhibited severe skeletal abnormalities (PMID: 19232556, 24644033); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 20577006, 21658220, 29776788, 20503319, 21573172, 28687525, 22791502, 24644033, 30945278, 32036093, 34008892, 32381727, 19232556) (less)
Pathogenic (Aug 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: SCV001246723.26 First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024	Number of individuals with the variant: 1
Pathogenic (Oct 01, 2010)	no assertion criteria provided Method: literature only	SPONDYLOMETAPHYSEAL DYSPLASIA, KOZLOWSKI TYPE Affected status: not provided Allele origin: germline	OMIM Accession: SCV000025460.4 First in ClinVar: Apr 04, 2013 Last updated: Oct 21, 2023	Publications: PubMed (5) PubMed: 19232556‚ 20577006‚ 20503319‚ 17879966‚ 21658220 Comment on evidence: Spondylometaphyseal Dysplasia, Kozlowski Type In 4 unrelated patients with the Kozlowski type of spondylometaphyseal dysplasia (SMDK; 184252), Krakow et al. (2009) identified a c.1781G-A transition … (more) Spondylometaphyseal Dysplasia, Kozlowski Type In 4 unrelated patients with the Kozlowski type of spondylometaphyseal dysplasia (SMDK; 184252), Krakow et al. (2009) identified a c.1781G-A transition in exon 11 of the TRPV4 gene, resulting in an arg594-to-his (R594H) substitution in the cytoplasmic S4 domain. In 2 of the 4 families, the mutation was not found in DNA from the unaffected parents, establishing the change as de novo. The mutation was associated with increased basal intracellular calcium ion concentration and intracellular calcium activity. The mutation occurs in a highly conserved residue and was not identified in at least 214 control chromosomes. In 12 probands with SMDK, Dai et al. (2010) identified heterozygosity for the R594H mutation and concluded that arg594 is a hotspot for mutation in SMDK. One of the patients did not show overt metaphyseal changes on x-ray and was considered to have a phenotype of intermediate severity between SMDK and brachyolmia (113500). Parastremmatic Dwarfism In a 7-year-old girl with parastremmatic dwarfism (168400), Nishimura et al. (2010) identified heterozygosity for the R594H mutation in the TRPV4 gene. Metatropic Dysplasia In a mother and 2 sons (patients 5, 6, and 7) and 2 unrelated patients (10 and 11, previously reported by Kannu et al., 2007) with metatropic dysplasia (MTD; 156530), Andreucci et al. (2011) identified heterozygosity for the R594H mutation in the TRPV4 gene. Andreucci et al. (2011) noted that the 2 sons exhibited intrafamilial variability, with one showing radiographic features that were more consistent with MTD and the other showing features more consistent with SMDK. The authors also identified heterozygosity for the R594H variant in 3 unrelated patients (patients 15, 16, and 22) clinically diagnosed with SMDK. (less)
Pathogenic (Oct 01, 2010)	no assertion criteria provided Method: literature only	PARASTREMMATIC DWARFISM Affected status: not provided Allele origin: germline	OMIM Accession: SCV000025461.4 First in ClinVar: Apr 04, 2013 Last updated: Oct 21, 2023	Publications: PubMed (5) PubMed: 19232556‚ 20577006‚ 20503319‚ 17879966‚ 21658220 Comment on evidence: Spondylometaphyseal Dysplasia, Kozlowski Type In 4 unrelated patients with the Kozlowski type of spondylometaphyseal dysplasia (SMDK; 184252), Krakow et al. (2009) identified a c.1781G-A transition … (more) Spondylometaphyseal Dysplasia, Kozlowski Type In 4 unrelated patients with the Kozlowski type of spondylometaphyseal dysplasia (SMDK; 184252), Krakow et al. (2009) identified a c.1781G-A transition in exon 11 of the TRPV4 gene, resulting in an arg594-to-his (R594H) substitution in the cytoplasmic S4 domain. In 2 of the 4 families, the mutation was not found in DNA from the unaffected parents, establishing the change as de novo. The mutation was associated with increased basal intracellular calcium ion concentration and intracellular calcium activity. The mutation occurs in a highly conserved residue and was not identified in at least 214 control chromosomes. In 12 probands with SMDK, Dai et al. (2010) identified heterozygosity for the R594H mutation and concluded that arg594 is a hotspot for mutation in SMDK. One of the patients did not show overt metaphyseal changes on x-ray and was considered to have a phenotype of intermediate severity between SMDK and brachyolmia (113500). Parastremmatic Dwarfism In a 7-year-old girl with parastremmatic dwarfism (168400), Nishimura et al. (2010) identified heterozygosity for the R594H mutation in the TRPV4 gene. Metatropic Dysplasia In a mother and 2 sons (patients 5, 6, and 7) and 2 unrelated patients (10 and 11, previously reported by Kannu et al., 2007) with metatropic dysplasia (MTD; 156530), Andreucci et al. (2011) identified heterozygosity for the R594H mutation in the TRPV4 gene. Andreucci et al. (2011) noted that the 2 sons exhibited intrafamilial variability, with one showing radiographic features that were more consistent with MTD and the other showing features more consistent with SMDK. The authors also identified heterozygosity for the R594H variant in 3 unrelated patients (patients 15, 16, and 22) clinically diagnosed with SMDK. (less)
Pathogenic (Oct 01, 2010)	no assertion criteria provided Method: literature only	METATROPIC DYSPLASIA Affected status: not provided Allele origin: germline	OMIM Accession: SCV001842644.2 First in ClinVar: Sep 12, 2021 Last updated: Oct 21, 2023	Publications: PubMed (5) PubMed: 19232556‚ 20577006‚ 20503319‚ 17879966‚ 21658220 Comment on evidence: Spondylometaphyseal Dysplasia, Kozlowski Type In 4 unrelated patients with the Kozlowski type of spondylometaphyseal dysplasia (SMDK; 184252), Krakow et al. (2009) identified a c.1781G-A transition … (more) Spondylometaphyseal Dysplasia, Kozlowski Type In 4 unrelated patients with the Kozlowski type of spondylometaphyseal dysplasia (SMDK; 184252), Krakow et al. (2009) identified a c.1781G-A transition in exon 11 of the TRPV4 gene, resulting in an arg594-to-his (R594H) substitution in the cytoplasmic S4 domain. In 2 of the 4 families, the mutation was not found in DNA from the unaffected parents, establishing the change as de novo. The mutation was associated with increased basal intracellular calcium ion concentration and intracellular calcium activity. The mutation occurs in a highly conserved residue and was not identified in at least 214 control chromosomes. In 12 probands with SMDK, Dai et al. (2010) identified heterozygosity for the R594H mutation and concluded that arg594 is a hotspot for mutation in SMDK. One of the patients did not show overt metaphyseal changes on x-ray and was considered to have a phenotype of intermediate severity between SMDK and brachyolmia (113500). Parastremmatic Dwarfism In a 7-year-old girl with parastremmatic dwarfism (168400), Nishimura et al. (2010) identified heterozygosity for the R594H mutation in the TRPV4 gene. Metatropic Dysplasia In a mother and 2 sons (patients 5, 6, and 7) and 2 unrelated patients (10 and 11, previously reported by Kannu et al., 2007) with metatropic dysplasia (MTD; 156530), Andreucci et al. (2011) identified heterozygosity for the R594H mutation in the TRPV4 gene. Andreucci et al. (2011) noted that the 2 sons exhibited intrafamilial variability, with one showing radiographic features that were more consistent with MTD and the other showing features more consistent with SMDK. The authors also identified heterozygosity for the R594H variant in 3 unrelated patients (patients 15, 16, and 22) clinically diagnosed with SMDK. (less)
Pathogenic (May 06, 2020)	no assertion criteria provided Method: clinical testing	Spondylometaphyseal dysplasia, Kozlowski type Affected status: yes Allele origin: germline	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City Accession: SCV001469219.1 First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021
not provided (-)	no classification provided Method: literature only	Neuromuscular disease Skeletal dysplasia Affected status: yes Allele origin: germline	GeneReviews Accession: SCV000148025.2 First in ClinVar: Dec 21, 2015 Last updated: Oct 01, 2022	Publications: BookShelf: NBK201366 BookShelf: NBK201366
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Comment:

The variant is not observed in the gnomAD v2.1.1 dataset. It is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.89; 3Cnet: 0.77). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000004994). Different missense changes at the same codon (p.Arg594Cys, p.Arg594Ser) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV001224354 , VCV001484191). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

Comment:

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 594 of the TRPV4 protein (p.Arg594His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with spondylometaphyseal dysplasia, Kozlowski type as well as other related skeletal dysplasias (PMID: 19232556, 20503319, 20577006, 21658220). ClinVar contains an entry for this variant (Variation ID: 4994). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TRPV4 protein function. Experimental studies have shown that this missense change affects TRPV4 function (PMID: 19232556, 21573172). For these reasons, this variant has been classified as Pathogenic.

Comment:

The c.1781G>A (p.R594H) alteration is located in exon 11 (coding exon 10) of the TRPV4 gene. This alteration results from a G to A substitution at nucleotide position 1781, causing the arginine (R) at amino acid position 594 to be replaced by a histidine (H). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been detected in multiple individuals with Kozlowski type spondylometaphyseal dysplasia and metatropic dysplasia, including some cases of reported de novo occurrence (Krakow, 2009; Dai, 2010; Andreucci, 2011; Zhang, 2015; Bieganski, 2017; Hsu, 2019). Another alteration at the same codon, c.1780C>A (p.R594S), has been described in an individual with metatropic dysplasia (Andreucci, 2011). This amino acid position is highly conserved in available vertebrate species. Functional analysis demonstrated that the p.R594H alteration altered basal calcium channel activity in vitro (Krakow, 2009). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.

Comment:

Published functional studies demonstrate that R594H leads to increased constitutive and agonist-responsive activity, and R594 transgenic mice exhibited severe skeletal abnormalities (PMID: 19232556, 24644033); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 20577006, 21658220, 29776788, 20503319, 21573172, 28687525, 22791502, 24644033, 30945278, 32036093, 34008892, 32381727, 19232556)

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
Phenotype-driven variant filtration strategy in exome sequencing toward a high diagnostic yield and identification of 85 novel variants in 400 patients with rare Mendelian disorders.	Marinakis NM	American journal of medical genetics. Part A	2021	PMID: 34008892
Diagnostic yield and clinical impact of exome sequencing in early-onset scoliosis (EOS).	Zhao S	Journal of medical genetics	2021	PMID: 32381727
Autosomal Dominant TRPV4 Disorders.	Adam MP	-	2020	PMID: 24830047
Next-generation sequencing identifies TRPV4-related skeletal dysplasia in a boy with progressive bowlegs.	Hsu RH	Pediatrics and neonatology	2019	PMID: 29776788
SMD Kozlowski type caused by p.Arg594His substitution in TRPV4 reveals abnormal ossification and notochordal remnants in discs and vertebrae.	Bieganski T	European journal of medical genetics	2017	PMID: 28687525
A pilot study of gene testing of genetic bone dysplasia using targeted next-generation sequencing.	Zhang H	Journal of human genetics	2015	PMID: 26377240
TRPV4 related skeletal dysplasias: a phenotypic spectrum highlighted byclinical, radiographic, and molecular studies in 21 new families.	Andreucci E	Orphanet journal of rare diseases	2011	PMID: 21658220
Increased basal activity is a key determinant in the severity of human skeletal dysplasia caused by TRPV4 mutations.	Loukin S	PloS one	2011	PMID: 21573172
Novel and recurrent TRPV4 mutations and their association with distinct phenotypes within the TRPV4 dysplasia family.	Dai J	Journal of medical genetics	2010	PMID: 20577006
Spondylo-epiphyseal dysplasia, Maroteaux type (pseudo-Morquio syndrome type 2), and parastremmatic dysplasia are caused by TRPV4 mutations.	Nishimura G	American journal of medical genetics. Part A	2010	PMID: 20503319
Mutations in the gene encoding the calcium-permeable ion channel TRPV4 produce spondylometaphyseal dysplasia, Kozlowski type and metatropic dysplasia.	Krakow D	American journal of human genetics	2009	DOI: 10.1016/j.ajhg.2009.01.021
Mutations in the gene encoding the calcium-permeable ion channel TRPV4 produce spondylometaphyseal dysplasia, Kozlowski type and metatropic dysplasia.	Krakow D	American journal of human genetics	2009	PMID: 19232556
Metatropic dysplasia: clinical and radiographic findings in 11 patients demonstrating long-term natural history.	Kannu P	American journal of medical genetics. Part A	2007	PMID: 17879966
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Text-mined citations for rs77975504 ...

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 25, 2024

ClinVar Genomic variation as it relates to human health

NM_021625.5(TRPV4):c.1781G>A (p.Arg594His)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs77975504 ...