NM_006005.3(WFS1):c.1957C>T (p.Arg653Cys) AND not provided

Clinical significance:Conflicting interpretations of pathogenicity, Likely benign(1);Uncertain significance(1) (Last evaluated: Nov 14, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:

Allele description [Variation Report for NM_006005.3(WFS1):c.1957C>T (p.Arg653Cys)]

NM_006005.3(WFS1):c.1957C>T (p.Arg653Cys)

WFS1:wolframin ER transmembrane glycoprotein [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
NM_006005.3(WFS1):c.1957C>T (p.Arg653Cys)
Other names:
p.R653C:CGC>TGC; NM_001145853.1(WFS1):c.1957C>T(p.Arg653Cys); NM_006005.3(WFS1):c.1957C>T(p.Arg653Cys)
  • NC_000004.12:g.6301752C>T
  • NG_011700.1:g.36903C>T
  • NM_001145853.1:c.1957C>T
  • NM_006005.3:c.1957C>TMANE SELECT
  • NP_001139325.1:p.Arg653Cys
  • NP_005996.2:p.Arg653Cys
  • LRG_1417t1:c.1957C>T
  • LRG_1417:g.36903C>T
  • LRG_1417p1:p.Arg653Cys
  • NC_000004.11:g.6303479C>T
  • O76024:p.Arg653Cys
Protein change:
UniProtKB: O76024#VAR_014037; dbSNP: rs201064551
NCBI 1000 Genomes Browser:
Molecular consequence:
  • NM_001145853.1:c.1957C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_006005.3:c.1957C>T - missense variant - [Sequence Ontology: SO:0001583]


MedGen: CN517202

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
SCV000252535GeneDxcriteria provided, single submitter
Uncertain significance
(Dec 6, 2012)
germlineclinical testing

Citation Link,

SCV001629615Invitaecriteria provided, single submitter
Likely benign
(Nov 14, 2020)
germlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing



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]

Details of each submission

From GeneDx, SCV000252535.11

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided


p.Arg653Cys (CGC>TGC):c.1957 C>T in exon 8 of the WFS1 gene (NM_006005.3). The R456H missense substitution in the WFS1 gene has been published in association with type 1 diabetes in a Japanese population where it was found at a significantly increased frequency in patients with type 1 diabetes compared to a control group (Awata et al., 2000). The amino acid change is conservative in that both Arginine and Histidine are positively charged amino acids. This change occurs at a position in the WFS1 protein that is highly conserved. Therefore, based on the currently available information, it is unclear whether R456H is a disease-causing mutation or a rare benign variant. The variant is found in MITONUC-MITOP panel(s).

OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV001629615.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jul 7, 2021

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