NM_005535.3(IL12RB1):c.1132G>A (p.Gly378Arg) AND Mendelian susceptibility to mycobacterial diseases due to complete IL12RB1 deficiency

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Sep 24, 2021
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:: RCV001123248.10

Allele description [Variation Report for NM_005535.3(IL12RB1):c.1132G>A (p.Gly378Arg)]

NM_005535.3(IL12RB1):c.1132G>A (p.Gly378Arg)

Gene:

IL12RB1:interleukin 12 receptor subunit beta 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

19p13.11

Genomic location:

Preferred name:

NM_005535.3(IL12RB1):c.1132G>A (p.Gly378Arg)

HGVS:

NC_000019.10:g.18069603C>T
NG_007366.2:g.34347G>A
NM_001290023.2:c.1132G>A
NM_001290024.1:c.1252G>A
NM_005535.3:c.1132G>AMANE SELECT
NP_001276952.1:p.Gly378Arg
NP_001276953.1:p.Gly418Arg
NP_005526.1:p.Gly378Arg
LRG_72t1:c.1132G>A
LRG_72:g.34347G>A
NC_000019.9:g.18180413C>T
NM_005535.1:c.1132G>A
NM_005535.2:c.1132G>A

Protein change:

G378R

Links:

dbSNP: rs401502

NCBI 1000 Genomes Browser:

rs401502

Molecular consequence:

NM_001290023.2:c.1132G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001290024.1:c.1252G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_005535.3:c.1132G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Mendelian susceptibility to mycobacterial diseases due to complete IL12RB1 deficiency
Synonyms:: IL12RB1 DEFICIENCY; Immunodeficiency 30
Identifiers:: MONDO: MONDO:0013955; MedGen: C4013949; Orphanet: 319552; OMIM: 614891

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TRA2A transformer 2 alpha homolog [Homo sapiens]
TRA2A transformer 2 alpha homolog [Homo sapiens]
Gene ID:29896

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001282068	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Benign (Apr 27, 2017)	germline	clinical testing	Citation Link,
SCV001386959	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Sep 24, 2021)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 11313259, 11992283, 16088278, 21057261, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001282068

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSL Variant Classification Criteria 13 December 2019)

Benign
(Apr 27, 2017)

germline

clinical testing

Citation Link,

SCV001386959

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Sep 24, 2021)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

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

Citations

PubMed

Missense mutation of the interleukin-12 receptor beta1 chain-encoding gene is associated with impaired immunity against Mycobacterium avium complex infection.

Sakai T, Matsuoka M, Aoki M, Nosaka K, Mitsuya H.

Blood. 2001 May 1;97(9):2688-94.

PubMed [citation]

PMID:: 11313259

Clinical and genetic heterogeneity of inherited autosomal recessive susceptibility to disseminated Mycobacterium bovis bacille calmette-guérin infection.

Elloumi-Zghal H, Barbouche MR, Chemli J, Béjaoui M, Harbi A, Snoussi N, Abdelhak S, Dellagi K.

J Infect Dis. 2002 May 15;185(10):1468-75. Epub 2002 Apr 30.

PubMed [citation]

PMID:: 11992283

See all PubMed Citations (5)

Details of each submission

From Illumina Laboratory Services, Illumina, SCV001282068.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not 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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.

#	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 Invitae, SCV001386959.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change replaces glycine with arginine at codon 378 of the IL12RB1 protein (p.Gly378Arg). The glycine residue is weakly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs401502, ExAC 0.006%). This missense change has been observed in individual(s) with mycobacterial disease (PMID: 11313259, 11992283, 16088278). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change does not substantially affect IL12RB1 function (PMID: 21057261). 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

Last Updated: Feb 4, 2024

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