NM_003331.5(TYK2):c.3310C>G (p.Pro1104Ala) AND Immunodeficiency 35

Clinical significance:Benign/Likely benign (Last evaluated: Dec 4, 2020)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
3 submissions [Details]
Record status:
current
Accession:
RCV000528354.5

Allele description [Variation Report for NM_003331.5(TYK2):c.3310C>G (p.Pro1104Ala)]

NM_003331.5(TYK2):c.3310C>G (p.Pro1104Ala)

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.3310C>G (p.Pro1104Ala)
Other names:
p.P1104A:CCC>GCC; TYK2, PRO1104ALA (rs34536443)
HGVS:
  • NC_000019.10:g.10352442G>C
  • NG_007872.1:g.33131C>G
  • NM_003331.5:c.3310C>GMANE SELECT
  • NP_003322.3:p.Pro1104Ala
  • LRG_121t1:c.3310C>G
  • LRG_121:g.33131C>G
  • NC_000019.9:g.10463118G>C
  • NM_003331.4:c.3310C>G
  • P29597:p.Pro1104Ala
Protein change:
P1104A; PRO1104ALA
Links:
UniProtKB: P29597#VAR_041874; OMIM: 176941.0007; dbSNP: rs34536443
NCBI 1000 Genomes Browser:
rs34536443
Molecular consequence:
  • NM_003331.5:c.3310C>G - 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

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000410277Illumina Clinical Services Laboratory,Illuminacriteria provided, single submitter
Likely benign
(Apr 27, 2017)
germlineclinical testing

Citation Link,

SCV000645761Invitaecriteria provided, single submitter
Benign
(Dec 4, 2020)
germlineclinical testing

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

SCV001572334OMIMno assertion criteria providedPathogenic
(Apr 26, 2021)
germlineliterature only

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only

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

Tuberculosis and impaired IL-23-dependent IFN-γ immunity in humans homozygous for a common TYK2 missense variant.

Boisson-Dupuis S, Ramirez-Alejo N, Li Z, Patin E, Rao G, Kerner G, Lim CK, Krementsov DN, Hernandez N, Ma CS, Zhang Q, Markle J, Martinez-Barricarte R, Payne K, Fisch R, Deswarte C, Halpern J, Bouaziz M, Mulwa J, Sivanesan D, Lazarov T, Naves R, et al.

Sci Immunol. 2018 Dec 21;3(30). doi:pii: eaau8714. 10.1126/sciimmunol.aau8714.

PubMed [citation]
PMID:
30578352
PMCID:
PMC6341984
See all PubMed Citations (3)

Details of each submission

From Illumina Clinical Services Laboratory,Illumina, SCV000410277.3

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

Description

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV000645761.3

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

From OMIM, SCV001572334.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (2)

Description

Boisson-Dupuis et al. (2018) found that homozygosity for the pro1104-to-ala (P1104A) variant of TYK2 was more frequent in a cohort of patients with tuberculosis from endemic areas than in ethnicity-adjusted controls (p = 8.37 x 10(-8); OR, 89.31; 95% CI, 14.7 to 1725). The P1104A allele is found in about 1 of 600 Europeans but is rare in East Asians. Moreover, the frequency of P1104A in Europeans has decreased over the past 4,000 years, consistent with purging of the variant by endemic tuberculosis. The authors found that the P1104A variant impaired cellular responses to IL23 (see 605580), but not to IFNA (IFNA1; 147660), IL10 (124092), or IL12 (see 161560). TYK2-P1104A docked to cytokine receptors, but it lacked catalytic activity. Thus, homozygotes for P1104A lacked the ability to induce IFNG (147570) via IL23, conferring a predisposition to severe mycobacterial diseases (IMD35; 611521), particularly primary tuberculosis.

Kerner et al. (2021) studied 1,013 ancient human genomes and determined that P1104A originated about 30,000 years ago and dropped significantly in frequency after the Bronze Age, about 2,000 years ago, due to strong negative selection. The authors estimated that the relative fitness reduction on P1104A homozygotes of about 20% is among the highest in the genome.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot providednot providednot providednot providednot provided

Last Updated: Aug 27, 2021

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