NM_003331.5(TYK2):c.691C>T (p.Arg231Trp) AND Immunodeficiency 35

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Jun 9, 2022
Review status:: criteria provided, conflicting classifications

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:: RCV001042442.10

Allele description [Variation Report for NM_003331.5(TYK2):c.691C>T (p.Arg231Trp)]

NM_003331.5(TYK2):c.691C>T (p.Arg231Trp)

Gene:

TYK2:tyrosine kinase 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

19p13.2

Genomic location:

Preferred name:

NM_003331.5(TYK2):c.691C>T (p.Arg231Trp)

HGVS:

NC_000019.10:g.10365837G>A
NG_007872.1:g.19736C>T
NM_003331.5:c.691C>TMANE SELECT
NP_003322.3:p.Arg231Trp
LRG_121t1:c.691C>T
LRG_121:g.19736C>T
NC_000019.9:g.10476513G>A
NM_003331.4:c.691C>T

Protein change:

R231W

Links:

dbSNP: rs201917359

NCBI 1000 Genomes Browser:

rs201917359

Molecular consequence:

NM_003331.5:c.691C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Immunodeficiency 35 (IMD35)
Synonyms:: HIES WITH ATYPICAL MYCOBACTERIOSIS, AUTOSOMAL RECESSIVE; HYPER-IgE SYNDROME WITH ATYPICAL MYCOBACTERIOSIS, AUTOSOMAL RECESSIVE; TYK2 DEFICIENCY; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0012682; MedGen: C1969086; OMIM: 611521

Recent activity

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SART-1 family [Arabidopsis thaliana]
SART-1 family [Arabidopsis thaliana]
gi|15237413|ref|NP_197180.1|

Protein
GBGT1 [Anser cygnoides]
GBGT1 [Anser cygnoides]
Gene ID:106044126

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001206122	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jun 9, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 31118190, 29725107, 28492532
SCV001522963	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jul 3, 2020)	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

SCV001206122

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Jun 9, 2022)

germline

clinical testing

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

SCV001522963

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jul 3, 2020)

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	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Identification of rare coding variants in TYK2 protective for rheumatoid arthritis in the Japanese population and their effects on cytokine signalling.

Motegi T, Kochi Y, Matsuda K, Kubo M, Yamamoto K, Momozawa Y.

Ann Rheum Dis. 2019 Aug;78(8):1062-1069. doi: 10.1136/annrheumdis-2019-215062. Epub 2019 May 22.

PubMed [citation]

PMID:: 31118190

Compound heterozygous TYK2 mutations underlie primary immunodeficiency with T-cell lymphopenia.

Nemoto M, Hattori H, Maeda N, Akita N, Muramatsu H, Moritani S, Kawasaki T, Maejima M, Ode H, Hachiya A, Sugiura W, Yokomaku Y, Horibe K, Iwatani Y.

Sci Rep. 2018 May 3;8(1):6956. doi: 10.1038/s41598-018-25260-8.

PubMed [citation]

PMID:: 29725107
PMCID:: PMC5934390

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001206122.5

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

Description

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: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Not Available"). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change affects TYK2 function (PMID: 29725107, 31118190). ClinVar contains an entry for this variant (Variation ID: 840450). This missense change has been observed in individual(s) with TYK2 deficiency (PMID: 29725107). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs201917359, gnomAD 0.06%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 231 of the TYK2 protein (p.Arg231Trp).

#	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 Baylor Genetics, SCV001522963.1

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

Description

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].

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

Last Updated: Sep 29, 2024

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