ClinVar Genomic variation as it relates to human health
NM_021625.5(TRPV4):c.2389G>A (p.Glu797Lys)
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_021625.5(TRPV4):c.2389G>A (p.Glu797Lys)
Variation ID: 18435 Accession: VCV000018435.18
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12q24.11 12: 109784385 (GRCh38) [ NCBI UCSC ] 12: 110222190 (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 Apr 4, 2013 Feb 14, 2024 Aug 10, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_021625.5:c.2389G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_067638.3:p.Glu797Lys missense NM_001177428.1:c.2248G>A NP_001170899.1:p.Glu750Lys missense NM_001177431.1:c.2287G>A NP_001170902.1:p.Glu763Lys missense NM_001177433.1:c.2068G>A NP_001170904.1:p.Glu690Lys missense NM_021625.4:c.[2389G>A] NM_147204.2:c.2209G>A NP_671737.1:p.Glu737Lys missense NC_000012.12:g.109784385C>T NC_000012.11:g.110222190C>T NG_017090.1:g.54023G>A LRG_372:g.54023G>A LRG_372t1:c.2389G>A LRG_372p1:p.Glu797Lys Q9HBA0:p.Glu797Lys - Protein change
- E690K, E750K, E763K, E737K
- Other names
- E797K
- Canonical SPDI
- NC_000012.12:109784384:C:T
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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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Allele frequency
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The frequency of the allele represented by this VCV record.
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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
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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
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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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TRPV4 | - | - |
GRCh38 GRCh37 |
1128 | 1143 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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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Pathogenic (2) |
criteria provided, single submitter
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- | RCV000005303.14 | |
Pathogenic (1) |
no assertion criteria provided
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Oct 1, 2010 | RCV000005304.12 | |
Pathogenic (1) |
no assertion criteria provided
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Oct 1, 2010 | RCV000023424.12 | |
not provided (1) |
no classification provided
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- | RCV000202566.10 | |
Pathogenic (1) |
criteria provided, single submitter
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May 30, 2019 | RCV001331193.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 16, 2019 | RCV001549550.10 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 10, 2023 | RCV001851964.13 | |
Pathogenic (1) |
criteria provided, single submitter
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- | RCV001823100.11 |
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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Pathogenic
(May 30, 2019)
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criteria provided, single submitter
Method: clinical testing
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Brachyrachia (short spine dysplasia)
Affected status: yes
Allele origin:
unknown
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Baylor Genetics
Accession: SCV001523177.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing [PMID 20425821, 20577006, 21573172, … (more)
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing [PMID 20425821, 20577006, 21573172, 26170305, 20503319] (less)
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Pathogenic
(Dec 16, 2019)
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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: SCV001769727.1
First in ClinVar: Aug 07, 2021 Last updated: Aug 07, 2021 |
Comment:
Reported previously in multiple individuals with TRPV4-related disorders including metatropic dysplasia and spondylo-epimetaphyseal dysplasia, Maroteaux-pseudo-Morquio type 2 (Camacho et al., 2010; Nishimura et al., 2010); … (more)
Reported previously in multiple individuals with TRPV4-related disorders including metatropic dysplasia and spondylo-epimetaphyseal dysplasia, Maroteaux-pseudo-Morquio type 2 (Camacho et al., 2010; Nishimura et al., 2010); Published functional studies demonstrate a damaging effect: increased basal activity and a reduced response to calmodulin (Loukin et al., 2015); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 12765694, 20676052, 23143559, 20577006, 26170305, 21573172, 20503319, 20425821) (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Spondylometaphyseal dysplasia, Kozlowski type
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
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Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
Accession: SCV002054015.1
First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022 |
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Scapuloperoneal spinal muscular atrophy
Affected status: yes
Allele origin:
germline
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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV002073066.1
First in ClinVar: Feb 05, 2022 Last updated: Feb 05, 2022 |
Comment:
The missense variant p.E797K in TRPV4 (NM_021625.5) has been reported in multiple affected individuals (Nishimura G et al; Dai J et al). It has been … (more)
The missense variant p.E797K in TRPV4 (NM_021625.5) has been reported in multiple affected individuals (Nishimura G et al; Dai J et al). It has been submitted to ClinVar as Pathogenic. The p.E797K variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.E797K missense variant is predicted to be damaging by both SIFT and PolyPhen2. The glutamic acid residue at codon 797 of TRPV4 is conserved in all mammalian species. The nucleotide c.2389 in TRPV4 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. (less)
Clinical Features:
Hurler syndrome (present)
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Pathogenic
(Aug 10, 2023)
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criteria provided, single submitter
Method: clinical testing
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Charcot-Marie-Tooth disease axonal type 2C
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV002242998.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
ClinVar contains an entry for this variant (Variation ID: 18435). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Glu797 … (more)
ClinVar contains an entry for this variant (Variation ID: 18435). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Glu797 amino acid residue in TRPV4. Other variant(s) that disrupt this residue have been observed in individuals with TRPV4-related conditions (PMID: 34529350), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this missense change affects TRPV4 function (PMID: 21573172, 26170305). 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. This missense change has been observed in individuals with clinical features of spondylometaphyseal dysplasia (PMID: 20425821, 20503319, 20577006; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 797 of the TRPV4 protein (p.Glu797Lys). (less)
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Pathogenic
(Oct 01, 2010)
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no assertion criteria provided
Method: literature only
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SPONDYLOEPIPHYSEAL DYSPLASIA, MAROTEAUX TYPE
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000025482.3
First in ClinVar: Apr 04, 2013 Last updated: Oct 21, 2023 |
Comment on evidence:
Spondylometaphyseal Dysplasia, Kozlowski Type In a patient with the Kozlowski type of spondylometaphyseal dysplasia (SMDK; 184252), Dai et al. (2010) identified heterozygosity for a c.2389G-A … (more)
Spondylometaphyseal Dysplasia, Kozlowski Type In a patient with the Kozlowski type of spondylometaphyseal dysplasia (SMDK; 184252), Dai et al. (2010) identified heterozygosity for a c.2389G-A transition in exon 15 of the TRPV4 gene, resulting in a glu797-to-lys (E797K) substitution at an evolutionarily conserved residue in the cytoplasmic domain. The authors noted that this was the first SMDK patient to be reported with a mutation in exon 15, which otherwise appears to be a hotspot for mutations causing metatropic dysplasia (MTD; 156530). Spondylometaphyseal Dysplasia, Maroteaux Type In an adult woman with the Maroteaux type of spondyloepiphyseal dysplasia (184095), Nishimura et al. (2010) identified heterozygosity for the E797K mutation in the TRPV4 gene. Metatropic Dysplasia Camacho et al. (2010) identified a heterozygous E797K mutation in a patient with a mild form of metatropic dysplasia (MTD; 156530), with little or no scoliosis, mild platyspondyly, mild metaphyseal widening, and carpal ossification delay. (less)
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Pathogenic
(Oct 01, 2010)
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no assertion criteria provided
Method: literature only
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SPONDYLOMETAPHYSEAL DYSPLASIA, KOZLOWSKI TYPE
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000025481.3
First in ClinVar: Apr 04, 2013 Last updated: Oct 21, 2023 |
Comment on evidence:
Spondylometaphyseal Dysplasia, Kozlowski Type In a patient with the Kozlowski type of spondylometaphyseal dysplasia (SMDK; 184252), Dai et al. (2010) identified heterozygosity for a c.2389G-A … (more)
Spondylometaphyseal Dysplasia, Kozlowski Type In a patient with the Kozlowski type of spondylometaphyseal dysplasia (SMDK; 184252), Dai et al. (2010) identified heterozygosity for a c.2389G-A transition in exon 15 of the TRPV4 gene, resulting in a glu797-to-lys (E797K) substitution at an evolutionarily conserved residue in the cytoplasmic domain. The authors noted that this was the first SMDK patient to be reported with a mutation in exon 15, which otherwise appears to be a hotspot for mutations causing metatropic dysplasia (MTD; 156530). Spondylometaphyseal Dysplasia, Maroteaux Type In an adult woman with the Maroteaux type of spondyloepiphyseal dysplasia (184095), Nishimura et al. (2010) identified heterozygosity for the E797K mutation in the TRPV4 gene. Metatropic Dysplasia Camacho et al. (2010) identified a heterozygous E797K mutation in a patient with a mild form of metatropic dysplasia (MTD; 156530), with little or no scoliosis, mild platyspondyly, mild metaphyseal widening, and carpal ossification delay. (less)
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Pathogenic
(Oct 01, 2010)
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no assertion criteria provided
Method: literature only
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METATROPIC DYSPLASIA
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000044715.3
First in ClinVar: Apr 04, 2013 Last updated: Oct 21, 2023 |
Comment on evidence:
Spondylometaphyseal Dysplasia, Kozlowski Type In a patient with the Kozlowski type of spondylometaphyseal dysplasia (SMDK; 184252), Dai et al. (2010) identified heterozygosity for a c.2389G-A … (more)
Spondylometaphyseal Dysplasia, Kozlowski Type In a patient with the Kozlowski type of spondylometaphyseal dysplasia (SMDK; 184252), Dai et al. (2010) identified heterozygosity for a c.2389G-A transition in exon 15 of the TRPV4 gene, resulting in a glu797-to-lys (E797K) substitution at an evolutionarily conserved residue in the cytoplasmic domain. The authors noted that this was the first SMDK patient to be reported with a mutation in exon 15, which otherwise appears to be a hotspot for mutations causing metatropic dysplasia (MTD; 156530). Spondylometaphyseal Dysplasia, Maroteaux Type In an adult woman with the Maroteaux type of spondyloepiphyseal dysplasia (184095), Nishimura et al. (2010) identified heterozygosity for the E797K mutation in the TRPV4 gene. Metatropic Dysplasia Camacho et al. (2010) identified a heterozygous E797K mutation in a patient with a mild form of metatropic dysplasia (MTD; 156530), with little or no scoliosis, mild platyspondyly, mild metaphyseal widening, and carpal ossification delay. (less)
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not provided
(-)
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no classification provided
Method: literature only
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Neuromuscular disease
Skeletal dysplasia
Affected status: yes
Allele origin:
germline
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GeneReviews
Accession: SCV000148042.2
First in ClinVar: Dec 21, 2015 Last updated: Oct 01, 2022 |
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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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Molecular diagnosis in a cohort of 114 patients with rare skeletal dysplasias. | Silveira KC | American journal of medical genetics. Part C, Seminars in medical genetics | 2021 | PMID: 34529350 |
Autosomal Dominant TRPV4 Disorders. | Adam MP | - | 2020 | PMID: 24830047 |
A channelopathy mechanism revealed by direct calmodulin activation of TrpV4. | Loukin SH | Proceedings of the National Academy of Sciences of the United States of America | 2015 | PMID: 26170305 |
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 |
Dominant TRPV4 mutations in nonlethal and lethal metatropic dysplasia. | Camacho N | American journal of medical genetics. Part A | 2010 | PMID: 20425821 |
Text-mined citations for rs267607149 ...
HelpRecord last updated Apr 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.