VCV001687523.4 - ClinVar

NM_000074.3(CD40LG):c.158_161del

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(2)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000074.3(CD40LG):c.158_161del

Variation ID: 1687523 Accession: VCV001687523.4

Type and length

Microsatellite, 4 bp

Location

Cytogenetic: Xq26.3 X: 136650262-136650265 (GRCh38) [ NCBI UCSC ] X: 135732421-135732424 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Jun 3, 2022	Feb 14, 2024	May 22, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_000074.3:c.158_161del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice acceptor
NC_000023.11:g.136650263TAGA[1]
NC_000023.10:g.135732422TAGA[1]
NG_007280.1:g.7087TAGA[1]
LRG_141:g.7087TAGA[1]

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000023.11:136650261:ATAGATAGA:ATAGA

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
CD40LG		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	277	457

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Hyper-IgM syndrome type 1	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	May 22, 2022	RCV002251205.4

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (May 22, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hyper-IgM syndrome type 1 Affected status: yes Allele origin: germline	3billion Accession: SCV002521723.1 First in ClinVar: Jun 03, 2022 Last updated: Jun 03, 2022	Publications: PubMed (3) PubMed: 24631270‚ 24768948‚ 7717401 Comment: The variant is not observed in the gnomAD v2.1.1 dataset. Canonical splice site: predicted to alter splicing and result in a loss or disruption of … (more) The variant is not observed in the gnomAD v2.1.1 dataset. Canonical splice site: predicted to alter splicing and result in a loss or disruption of normal protein function. Multiple pathogenic loss-of-function variants are reported downstream of the variant. The variant has been reported to be associated with CD40LG related disorder (PMID: 24631270, 24768948 ). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Cellulitis (present) , Neutropenia (present)
Pathogenic (Feb 02, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Hyper-IgM syndrome type 1 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003445200.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024	Publications: PubMed (3) PubMed: 7717401‚ 24768948‚ 15319456 Comment: For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individual(s) with hyper-IgM syndrome (PMID: 7717401, … (more) For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individual(s) with hyper-IgM syndrome (PMID: 7717401, 24768948). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ile53Lysfs*13) in the CD40LG gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CD40LG are known to be pathogenic (PMID: 15319456). (less)

Comment:

The variant is not observed in the gnomAD v2.1.1 dataset. Canonical splice site: predicted to alter splicing and result in a loss or disruption of normal protein function. Multiple pathogenic loss-of-function variants are reported downstream of the variant. The variant has been reported to be associated with CD40LG related disorder (PMID: 24631270, 24768948 ). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

Comment:

For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individual(s) with hyper-IgM syndrome (PMID: 7717401, 24768948). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ile53Lysfs*13) in the CD40LG gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CD40LG are known to be pathogenic (PMID: 15319456).

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Clinical, molecular, and T cell subset analyses in a small cohort of Chinese patients with hyper-IgM syndrome type 1.	Tang WJ	Human immunology	2014	PMID: 24768948
Whole-exome sequence analysis of ataxia telangiectasia-like phenotype.	Hasegawa S	Journal of the neurological sciences	2014	PMID: 24631270
The hyper IgM syndrome--an evolving story.	Etzioni A	Pediatric research	2004	PMID: 15319456
Characterization of nine novel mutations in the CD40 ligand gene in patients with X-linked hyper IgM syndrome of various ancestry.	Macchi P	American journal of human genetics	1995	PMID: 7717401

Text-mined citations for this variant ...

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000074.3(CD40LG):c.158_161del

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...