X-136659390-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000074.3(CD40LG):c.761C>T(p.Thr254Met) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T254K) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 22)
• Consequence: CD40LG NM_000074.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 3.84

Genes affected

CD40LG (HGNC:11935): (CD40 ligand) The protein encoded by this gene is expressed on the surface of T cells. It regulates B cell function by engaging CD40 on the B cell surface. A defect in this gene results in an inability to undergo immunoglobulin class switch and is associated with hyper-IgM syndrome. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_000074.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-136659390-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 530671.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.947
• PP5: Variant X-136659390-C-T is Pathogenic according to our data. Variant chrX-136659390-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 35814.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-136659390-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CD40LG	NM_000074.3	c.761C>T	p.Thr254Met	missense_variant	5/5	ENST00000370629.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CD40LG	ENST00000370629.7	c.761C>T	p.Thr254Met	missense_variant	5/5	1	NM_000074.3	P1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hyper-IgM syndrome type 1 Pathogenic:2 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 02, 2022	This variant is also known as 782C>T. This missense change has been observed in individuals with a milder phenotype and X-linked hyper IgM syndrome (PMID: 10484640, 17351759, 19575287, 25541662). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 254 of the CD40LG protein (p.Thr254Met). ClinVar contains an entry for this variant (Variation ID: 35814). For these reasons, this variant has been classified as Pathogenic. 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Sep 28, 2021	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

Glycogen storage disease, type II Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Mar 20, 2024

Variant summary: GAA c.761C>T (p.Ser254Leu) results in a non-conservative amino acid change located in the Galactose mutarotase, N-terminal barrel domain (IPR031727) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00019 in 282470 control chromosomes, predominantly at a frequency of 0.0028 within the East Asian subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in GAA causing Glycogen Storage Disease, Type 2 (Pompe Disease) (0.00019 vs 0.0042), allowing no conclusion about variant significance. c.761C>T has been reported in the literature as a complex allele in cis with c.752C>T (p.Ser251Leu) in settings of newborn screening for Glycogen Storage Disease, Type 2 (Pompe Disease) (example, Labrousse_2010, Chien_2011, Liao_2014). This complex allele has been observed as a homozygous and compound heterozygous genotype in the ascertained reports among newborns with screening enzyme activity below the cutoff value (example, Liao_2014). These report(s) do not provide unequivocal conclusions about association of the variant in isolation with Glycogen Storage Disease, Type 2 (Pompe Disease). Co-occurrences of this complex allele in cis with other pathogenic variant(s) have been reported in the literature (GAA c.1411_1414del , p.E471PfsX5), providing supporting evidence for a benign role (example, Larousse_2010, Liao_2014). To our knowledge, no variant specific experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (VUS, n=2; P/LP, n=6). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Pathogenic	0.65	D
BayesDel_noAF	Pathogenic	0.69
Cadd	Uncertain	24
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	D;D
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.86	D;D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Pathogenic	1.2	D
MutationAssessor	Uncertain	2.8	M;.
MutationTaster	Benign	0.93	A;A
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-4.3	D;D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		1.0	D;D
Vest4		0.87
MutPred		0.68		Loss of disorder (P = 0.0982);.;
MVP		0.99
MPC		1.3
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.91
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs193922136; hg19: chrX-135741549; COSMIC: COSV101033584;