NM_018979.4(WNK1):c.6310A>G (p.Lys2104Glu) AND multiple conditions

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Oct 27, 2021
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000823615.2

Allele description [Variation Report for NM_018979.4(WNK1):c.6310A>G (p.Lys2104Glu)]

NM_018979.4(WNK1):c.6310A>G (p.Lys2104Glu)

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.6310A>G (p.Lys2104Glu)

HGVS:

NC_000012.12:g.897543A>G
NG_007984.3:g.149485A>G
NM_001184985.2:c.7090A>G
NM_014823.3:c.5566A>G
NM_018979.4:c.6310A>GMANE SELECT
NM_213655.5:c.7066A>G
NP_001171914.1:p.Lys2364Glu
NP_055638.2:p.Lys1856Glu
NP_061852.3:p.Lys2104Glu
NP_998820.3:p.Lys2356Glu
LRG_247t1:c.6310A>G
LRG_247t2:c.7066A>G
LRG_247:g.149485A>G
LRG_247p1:p.Lys2104Glu
LRG_247p2:p.Lys2356Glu
NC_000012.11:g.1006709A>G
NM_018979.3:c.6310A>G

Protein change:

K1856E

Links:

dbSNP: rs1310976331

NCBI 1000 Genomes Browser:

rs1310976331

Molecular consequence:

NM_001184985.2:c.7090A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_014823.3:c.5566A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_018979.4:c.6310A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_213655.5:c.7066A>G - 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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000964480	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Sep 19, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002815300	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Oct 27, 2021)	unknown	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

SCV000964480

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Sep 19, 2018)

germline

clinical testing

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

SCV002815300

Fulgent Genetics, Fulgent Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Oct 27, 2021)

unknown

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	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
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):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Invitae, SCV000964480.1

#	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 lysine with glutamic acid at codon 2104 of the WNK1 protein (p.Lys2104Glu). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with WNK1-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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

From Fulgent Genetics, Fulgent Genetics, SCV002815300.1

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

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

Last Updated: Jan 7, 2023

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