NM_000074.3(CD40LG):c.773T>C (p.Leu258Ser) AND Hyper-IgM syndrome type 1

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jun 29, 2018
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000690645.7

Allele description [Variation Report for NM_000074.3(CD40LG):c.773T>C (p.Leu258Ser)]

NM_000074.3(CD40LG):c.773T>C (p.Leu258Ser)

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.773T>C (p.Leu258Ser)

HGVS:

NC_000023.11:g.136659402T>C
NG_007280.1:g.16226T>C
NM_000074.3:c.773T>CMANE SELECT
NP_000065.1:p.Leu258Ser
NP_000065.1:p.Leu258Ser
LRG_141t1:c.773T>C
LRG_141:g.16226T>C
LRG_141p1:p.Leu258Ser
NC_000023.10:g.135741561T>C
NM_000074.2:c.773T>C

Protein change:

L258S

Links:

dbSNP: rs1569377884

NCBI 1000 Genomes Browser:

rs1569377884

Molecular consequence:

NM_000074.3:c.773T>C - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000818342	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jun 29, 2018)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 9746782, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000818342

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jun 29, 2018)

germline

clinical testing

PubMed (2)
[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

Mutations of the CD40 ligand gene and its effect on CD40 ligand expression in patients with X-linked hyper IgM syndrome.

Seyama K, Nonoyama S, Gangsaas I, Hollenbaugh D, Pabst HF, Aruffo A, Ochs HD.

Blood. 1998 Oct 1;92(7):2421-34.

PubMed [citation]

PMID:: 9746782

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. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000818342.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

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. Experimental studies have shown that cells carrying this missense change express CD40L protein, but that it does not bind CD40-Ig (PMID: 9746782). This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with serine at codon 258 of the CD40LG protein (p.Leu258Ser). The leucine residue is highly conserved and there is a large physicochemical difference between leucine and serine. This variant has been observed in several families affected with hyper IgM syndrome, however, clinical details for these families were not provided (PMID: 9746782).

#	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: Sep 29, 2024

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