NM_000074.3(CD40LG):c.431del (p.Gly144fs) AND Hyper-IgM syndrome type 1

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Oct 8, 2023
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:: RCV002834387.3

Allele description [Variation Report for NM_000074.3(CD40LG):c.431del (p.Gly144fs)]

NM_000074.3(CD40LG):c.431del (p.Gly144fs)

Gene:

CD40LG:CD40 ligand [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

Xq26.3

Genomic location:

Preferred name:

NM_000074.3(CD40LG):c.431del (p.Gly144fs)

HGVS:

NC_000023.11:g.136659060del
NG_007280.1:g.15884del
NM_000074.3:c.431delMANE SELECT
NP_000065.1:p.Gly144Aspfs
NP_000065.1:p.Gly144fs
LRG_141t1:c.431del
LRG_141:g.15884del
LRG_141p1:p.Gly144Aspfs
NC_000023.10:g.135741218del
NC_000023.10:g.135741219del
NM_000074.2:c.431delG

Protein change:

G144fs

Molecular consequence:

NM_000074.3:c.431del - frameshift variant - [Sequence Ontology: SO:0001589]

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
SCV003214305	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 8, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 30053428, 10366125, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003214305

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 8, 2023)

germline

clinical testing

PubMed (3)
[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

Clinical and molecular features of X-linked hyper IgM syndrome - An experience from North India.

Rawat A, Mathew B, Pandiarajan V, Jindal A, Sharma M, Suri D, Gupta A, Goel S, Karim A, Saikia B, Minz RW, Imai K, Nonoyama S, Ohara O, Giliani SC, Notarangelo LD, Chan KW, Lau YL, Singh S.

Clin Immunol. 2018 Oct;195:59-66. doi: 10.1016/j.clim.2018.07.013. Epub 2018 Jul 25.

PubMed [citation]

PMID:: 30053428
PMCID:: PMC6666391

An aggressive form of polyarticular arthritis in a man with CD154 mutation (X-linked hyper-IgM syndrome).

Webster EA, Khakoo AY, Mackus WJ, Karpusas M, Thomas DW, Davidson A, Christian CL, Lederman S.

Arthritis Rheum. 1999 Jun;42(6):1291-6.

PubMed [citation]

PMID:: 10366125

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003214305.2

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

Description

This sequence change creates a premature translational stop signal (p.Gly144Aspfs*5) in the CD40LG gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 118 amino acid(s) of the CD40LG protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with hyper IgM syndrome (PMID: 30053428). ClinVar contains an entry for this variant (Variation ID: 2013065). This variant disrupts a region of the CD40LG protein in which other variant(s) (p.Gly257Asp) have been determined to be pathogenic (PMID: 10366125; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

#	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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