ClinVar Miner

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

gnomAD frequency: 0.00002  dbSNP: rs146304351
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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics RCV000994976 SCV000615860 uncertain significance not provided 2022-03-30 criteria provided, single submitter clinical testing
Invitae RCV000684901 SCV000812362 uncertain significance Charcot-Marie-Tooth disease axonal type 2C 2023-10-26 criteria provided, single submitter clinical testing 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.
CeGaT Center for Human Genetics Tuebingen RCV000994976 SCV001148823 uncertain significance not provided 2019-06-01 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV001112861 SCV001270565 uncertain significance Brachyrachia (short spine dysplasia) 2017-04-27 criteria provided, single submitter clinical testing 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.
Illumina Laboratory Services, Illumina RCV001114213 SCV001272064 uncertain significance Scapuloperoneal spinal muscular atrophy 2017-04-27 criteria provided, single submitter clinical testing 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.
Illumina Laboratory Services, Illumina RCV001114214 SCV001272065 uncertain significance Metatropic dysplasia 2017-04-27 criteria provided, single submitter clinical testing 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.
Illumina Laboratory Services, Illumina RCV000684901 SCV001272066 uncertain significance Charcot-Marie-Tooth disease axonal type 2C 2017-04-27 criteria provided, single submitter clinical testing 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.
Illumina Laboratory Services, Illumina RCV001114215 SCV001272067 uncertain significance Neuronopathy, distal hereditary motor, autosomal dominant 8 2017-04-27 criteria provided, single submitter clinical testing 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.
Illumina Laboratory Services, Illumina RCV001114216 SCV001272068 likely benign Spondylometaphyseal dysplasia, Kozlowski type 2017-04-27 criteria provided, single submitter clinical testing 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.
Molecular Genetics Laboratory, London Health Sciences Centre RCV001173247 SCV001336330 uncertain significance Charcot-Marie-Tooth disease criteria provided, single submitter clinical testing
GeneDx RCV000994976 SCV002504565 likely benign not provided 2019-12-04 criteria provided, single submitter clinical testing See Variant Classification Assertion Criteria.
Ambry Genetics RCV002341214 SCV002645362 uncertain significance Inborn genetic diseases 2020-02-26 criteria provided, single submitter clinical testing 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.

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