NM_000074.3(CD40LG):c.107T>G (p.Met36Arg) AND Hyper-IgM syndrome type 1

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Feb 11, 2022
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:: RCV000011912.14

Allele description [Variation Report for NM_000074.3(CD40LG):c.107T>G (p.Met36Arg)]

NM_000074.3(CD40LG):c.107T>G (p.Met36Arg)

Gene:

CD40LG:CD40 ligand [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

Xq26.3

Genomic location:

Preferred name:

NM_000074.3(CD40LG):c.107T>G (p.Met36Arg)

HGVS:

NC_000023.11:g.136648355T>G
NG_007280.1:g.5179T>G
NM_000074.3:c.107T>GMANE SELECT
NP_000065.1:p.Met36Arg
NP_000065.1:p.Met36Arg
LRG_141t1:c.107T>G
LRG_141:g.5179T>G
LRG_141p1:p.Met36Arg
NC_000023.10:g.135730514T>G
NM_000074.2:c.107T>G
P29965:p.Met36Arg

Protein change:

M36R; MET36ARG

Links:

UniProtKB: P29965#VAR_007513; OMIM: 300386.0006; dbSNP: rs104894774

NCBI 1000 Genomes Browser:

rs104894774

Molecular consequence:

NM_000074.3:c.107T>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Hyper-IgM syndrome type 1
Synonyms:: Immunodeficiency with hyper IgM type 1; Hyper IgM immunodeficiency, X-linked; Hyper-IgM Immunodeficiency Syndrome, Type 1; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0010626; MedGen: C0398689; OMIM: 308230

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000032145	OMIM	no assertion criteria provided	Pathogenic (Feb 11, 1993)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000891219	Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Aug 14, 2018)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 7916370, 7679206, 1427881, 25741868
SCV001372829	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Feb 11, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 10559240, 7679206, 15358621, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000032145

OMIM

no assertion criteria provided

Pathogenic
(Feb 11, 1993)

germline

literature only

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

SCV000891219

Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Aug 14, 2018)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV001372829

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Feb 11, 2022)

germline

clinical testing

PubMed (4)
[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
not provided	germline	yes	1	not provided	not provided	1	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

CD40 ligand (CD40L) expression and B cell function in agammaglobulinemia with normal or elevated levels of IgM (HIM). Comparison of X-linked, autosomal recessive, and non-X-linked forms of the disease, and obligate carriers.

Callard RE, Smith SH, Herbert J, Morgan G, Padayachee M, Lederman S, Chess L, Kroczek RA, Fanslow WC, Armitage RJ.

J Immunol. 1994 Oct 1;153(7):3295-306.

PubMed [citation]

PMID:: 7916370

Mapping of the X-linked form of hyper-IgM syndrome (HIGM1) to Xq26 by close linkage to HPRT.

Padayachee M, Feighery C, Finn A, McKeown C, Levinsky RJ, Kinnon C, Malcolm S.

Genomics. 1992 Oct;14(2):551-3. No abstract available.

PubMed [citation]

PMID:: 1427881

See all PubMed Citations (7)

Details of each submission

From OMIM, SCV000032145.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In a boy with hyper-IgM syndrome-1 (HIGM1; 308230), Korthauer et al. (1993) described a T-to-G transversion of nucleotide 163 converting codon 36 from ATG (met) to AGG (arg). The mutation was located in the part of the gene encoding the transmembrane portion of the CD40 ligand.

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

From Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota, SCV000891219.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (4)

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

From Invitae, SCV001372829.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects CD40LG function (PMID: 10559240). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CD40LG protein function. ClinVar contains an entry for this variant (Variation ID: 11162). This missense change has been observed in individual(s) with X-linked hyper-IgM syndrome (PMID: 7679206, 15358621). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 36 of the CD40LG protein (p.Met36Arg).

#	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: Apr 6, 2024

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