NM_018979.4(WNK1):c.4864C>A (p.Pro1622Thr) AND multiple conditions

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Nov 2, 2023
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:: RCV003810187.2

Allele description [Variation Report for NM_018979.4(WNK1):c.4864C>A (p.Pro1622Thr)]

NM_018979.4(WNK1):c.4864C>A (p.Pro1622Thr)

Gene:

WNK1:WNK lysine deficient protein kinase 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

12p13.33

Genomic location:

Preferred name:

NM_018979.4(WNK1):c.4864C>A (p.Pro1622Thr)

HGVS:

NC_000012.12:g.885668C>A
NG_007984.3:g.137610C>A
NM_001184985.2:c.5644C>A
NM_014823.3:c.4123C>A
NM_018979.4:c.4864C>AMANE SELECT
NM_213655.5:c.5620C>A
NP_001171914.1:p.Pro1882Thr
NP_055638.2:p.Pro1375Thr
NP_061852.3:p.Pro1622Thr
NP_998820.3:p.Pro1874Thr
LRG_247t1:c.4864C>A
LRG_247t2:c.5620C>A
LRG_247:g.137610C>A
LRG_247p1:p.Pro1622Thr
LRG_247p2:p.Pro1874Thr
NC_000012.11:g.994834C>A

Protein change:

P1375T

Molecular consequence:

NM_001184985.2:c.5644C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_014823.3:c.4123C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_018979.4:c.4864C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_213655.5:c.5620C>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Neuropathy, hereditary sensory and autonomic, type 2A (HSAN2A)
Synonyms:: ACROOSTEOLYSIS, GIACCAI TYPE; ACROOSTEOLYSIS, NEUROGENIC; HSAN IIA; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0024309; MedGen: C2752089; Orphanet: 970; OMIM: 201300

Name:: Pseudohypoaldosteronism type 2C (PHA2C)
Identifiers:: MONDO: MONDO:0013778; MedGen: C1840391; Orphanet: 757; OMIM: 614492

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AFULGI_RS14605 [Archaeoglobus fulgidus DSM 8774]
AFULGI_RS14605 [Archaeoglobus fulgidus DSM 8774]
Gene ID:95969771

Gene
AFULGI_RS14635 [Archaeoglobus fulgidus DSM 8774]
AFULGI_RS14635 [Archaeoglobus fulgidus DSM 8774]
Gene ID:95969777

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004609805	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Nov 2, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004609805

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Nov 2, 2023)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

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

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004609805.1

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

Description

This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1874 of the WNK1 protein (p.Pro1874Thr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with WNK1-related conditions. 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 WNK1 protein function with a negative predictive value of 95%. 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.

#	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: Sep 29, 2024

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