X-120626901-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_001011551.3(C1GALT1C1):c.266C>T(p.Thr89Ile) variant causes a missense change involving the alteration of a conserved nucleotide. 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 (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: C1GALT1C1 NM_001011551.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.56

Genes affected

C1GALT1C1 (HGNC:24338): (C1GALT1 specific chaperone 1) This gene encodes a type II transmembrane protein that is similar to the core 1 beta1,3-galactosyltransferase 1, which catalyzes the synthesis of the core-1 structure, also known as Thomsen-Friedenreich antigen, on O-linked glycans. This gene product lacks the galactosyltransferase activity itself, but instead acts as a molecular chaperone required for the folding, stability and full activity of the core 1 beta1,3-galactosyltransferase 1. Mutations in this gene have been associated with Tn syndrome. Alternatively spliced transcript variants encoding the same protein have been identified. [provided by RefSeq, Dec 2009]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.962
• PP5: Variant X-120626901-G-A is Pathogenic according to our data. Variant chrX-120626901-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 2506572.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C1GALT1C1	NM_001011551.3	c.266C>T	p.Thr89Ile	missense_variant	2/2	ENST00000304661.6
C1GALT1C1	NM_152692.5	c.266C>T	p.Thr89Ile	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C1GALT1C1	ENST00000304661.6	c.266C>T	p.Thr89Ile	missense_variant	2/2	1	NM_001011551.3	P1
C1GALT1C1	ENST00000371313.2	c.266C>T	p.Thr89Ile	missense_variant	3/3	1		P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Atypical hemolytic-uremic syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

research

The Morris Kahn Laboratory of Human Genetics, Ben-Gurion University of the Negev

Jun 24, 2023

A de novo C1GALT1C1:c.266C>T;p.Thr89Ile variant was identified in a patient exhibiting early-onset atypical hemolytic uremic syndrome (aHUS), and was not present in the gnomAD database. This variant is situated in an area of remarkable evolutionary conservation. In vitro studies have demonstrated that this variant results in the generation of an exposed T-antigen on erythrocytes, which incites complement activation against these erythrocytes (Noam Hadar et al. 2023). This action potentially mirrors the mechanism of T-antigen mediated pneumococcal hemolytic uremic syndrome (Nicolas Burin des Roziers et al. 2015). In conclusion, the de novo Thr89Ile variant was absent from control samples, and the molecular mechanism it underlies leads to the exposure of a T-antigen in a manner similar to that observed in pneumococcal hemolytic uremic syndrome. Consequently, this variant is classified as pathogenic. -

Hemolytic uremic syndrome, atypical, 8, with rhizomelic short stature Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 11, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.79	D;D
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Uncertain	-0.049	T
MutationAssessor	Uncertain	2.9	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-5.6	D;D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.024	D;D
Sift4G	Benign	0.072	T;T
Polyphen		0.98	D;D
Vest4		0.96
MutPred		0.82		Gain of methylation at K92 (P = 0.0443);Gain of methylation at K92 (P = 0.0443);
MVP		0.93
MPC		0.47
ClinPred		0.99	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.78
gMVP		0.98

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-119760756;