NM_006005.3(WFS1):c.1219C>T (p.His407Tyr) AND not provided

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jan 15, 2025
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:: RCV001308356.9

Allele description [Variation Report for NM_006005.3(WFS1):c.1219C>T (p.His407Tyr)]

NM_006005.3(WFS1):c.1219C>T (p.His407Tyr)

Gene:

WFS1:wolframin ER transmembrane glycoprotein [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

4p16.1

Genomic location:

Preferred name:

NM_006005.3(WFS1):c.1219C>T (p.His407Tyr)

HGVS:

NC_000004.12:g.6301014C>T
NG_011700.1:g.36165C>T
NM_001145853.1:c.1219C>T
NM_006005.3:c.1219C>TMANE SELECT
NP_001139325.1:p.His407Tyr
NP_005996.2:p.His407Tyr
LRG_1417t1:c.1219C>T
LRG_1417:g.36165C>T
LRG_1417p1:p.His407Tyr
NC_000004.11:g.6302741C>T

Protein change:

H407Y

Links:

dbSNP: rs151244358

NCBI 1000 Genomes Browser:

rs151244358

Molecular consequence:

NM_001145853.1:c.1219C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_006005.3:c.1219C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided; RECLASSIFIED - ADRA2C POLYMORPHISM; RECLASSIFIED - ADRB1 POLYMORPHISM
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001497803	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 15, 2025)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 37277527, 28492532
SCV005882337	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Sep 9, 2024)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001497803

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 15, 2025)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV005882337

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(Sep 9, 2024)

germline

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	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

The genetic and clinical characteristics of WFS1 related diabetes in Chinese early onset type 2 diabetes.

Li Y, Gong S, Li M, Cai X, Liu W, Zhang S, Ma Y, Luo Y, Zhou L, Zhang X, Huang X, Gao X, Hu M, Li Y, Ren Q, Wang Y, Zhou X, Han X, Ji L.

Sci Rep. 2023 Jun 5;13(1):9127. doi: 10.1038/s41598-023-36334-7.

PubMed [citation]

PMID:: 37277527
PMCID:: PMC10241780

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, SCV001497803.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 407 of the WFS1 protein (p.His407Tyr). This variant is present in population databases (rs151244358, gnomAD 0.02%). This missense change has been observed in individual(s) with early-onset diabetes (PMID: 37277527). ClinVar contains an entry for this variant (Variation ID: 166583). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt WFS1 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

From GeneDx, SCV005882337.1

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

Description

Reported in a patient with type 2 diabetes in published literature (PMID: 37277527); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 37277527)

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

Last Updated: May 16, 2025

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