NM_021625.5(TRPV4):c.590A>G (p.Lys197Arg) AND Charcot-Marie-Tooth disease axonal type 2C

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jun 6, 2020
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001315769.14

Allele description [Variation Report for NM_021625.5(TRPV4):c.590A>G (p.Lys197Arg)]

NM_021625.5(TRPV4):c.590A>G (p.Lys197Arg)

Gene:

TRPV4:transient receptor potential cation channel subfamily V member 4 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

12q24.11

Genomic location:

Preferred name:

NM_021625.5(TRPV4):c.590A>G (p.Lys197Arg)

HGVS:

NC_000012.12:g.109803113T>C
NG_017090.1:g.35295A>G
NM_001177428.1:c.590A>G
NM_001177431.1:c.488A>G
NM_001177433.1:c.590A>G
NM_021625.5:c.590A>GMANE SELECT
NM_147204.2:c.590A>G
NP_001170899.1:p.Lys197Arg
NP_001170902.1:p.Lys163Arg
NP_001170904.1:p.Lys197Arg
NP_067638.3:p.Lys197Arg
NP_671737.1:p.Lys197Arg
LRG_372t1:c.590A>G
LRG_372:g.35295A>G
LRG_372p1:p.Lys197Arg
NC_000012.11:g.110240918T>C
NM_021625.4:c.590A>G
Q9HBA0:p.Lys197Arg

Protein change:

K163R; LYS197ARG

Links:

UniProtKB: Q9HBA0#VAR_064519; OMIM: 605427.0024; dbSNP: rs387906903

NCBI 1000 Genomes Browser:

rs387906903

Molecular consequence:

NM_001177428.1:c.590A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001177431.1:c.488A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001177433.1:c.590A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_021625.5:c.590A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_147204.2:c.590A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Charcot-Marie-Tooth disease axonal type 2C (HMSN2C)
Synonyms:: Charcot-Marie-Tooth disease type 2C; Hereditary motor and sensory neuropathy 2 C; CHARCOT-MARIE-TOOTH DISEASE, AXONAL, AUTOSOMAL DOMINANT, TYPE 2C; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0011633; MedGen: C1853710; OMIM: 606071

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001506360	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jun 6, 2020)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 22702953, 20425821, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001506360

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jun 6, 2020)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Structural and biochemical consequences of disease-causing mutations in the ankyrin repeat domain of the human TRPV4 channel.

Inada H, Procko E, Sotomayor M, Gaudet R.

Biochemistry. 2012 Aug 7;51(31):6195-206. Epub 2012 Jul 25.

PubMed [citation]

PMID:: 22702953
PMCID:: PMC3413242

Dominant TRPV4 mutations in nonlethal and lethal metatropic dysplasia.

Camacho N, Krakow D, Johnykutty S, Katzman PJ, Pepkowitz S, Vriens J, Nilius B, Boyce BF, Cohn DH.

Am J Med Genet A. 2010 May;152A(5):1169-77. doi: 10.1002/ajmg.a.33392.

PubMed [citation]

PMID:: 20425821
PMCID:: PMC4169191

See all PubMed Citations (3)

Details of each submission

From Invitae, SCV001506360.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has been reported to affect TRPV4 protein function (PMID: 22702953). This variant has been observed in individual(s) with metatropic dysplasia (PMID: 20425821). ClinVar contains an entry for this variant (Variation ID: 30471). This variant is not present in population databases (ExAC no frequency). This sequence change replaces lysine with arginine at codon 197 of the TRPV4 protein (p.Lys197Arg). The lysine residue is moderately conserved and there is a small physicochemical difference between lysine and arginine.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jul 15, 2024

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