Submissions for variant NM_000074.3(CD40LG):c.761C>T (p.Thr254Met)

dbSNP: rs193922136

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004528136	SCV000695312	pathogenic	Glycogen storage disease, type II	2024-03-20	criteria provided, single submitter	clinical testing	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.
Invitae	RCV000029466	SCV000939437	pathogenic	Hyper-IgM syndrome type 1	2022-12-02	criteria provided, single submitter	clinical testing	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.
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000029466	SCV002764963	pathogenic	Hyper-IgM syndrome type 1	2021-09-28	criteria provided, single submitter	clinical testing
GeneReviews	RCV000029466	SCV001364082	not provided	Hyper-IgM syndrome type 1		no assertion provided	literature only