X-120626614-C-T

Position:

• chrX-120626614-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001011551.3(C1GALT1C1):​c.553G>A​(p.Gly185Arg) 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: C1GALT1C1 NM_001011551.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.73

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 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.963

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
C1GALT1C1	NM_001011551.3	c.553G>A	p.Gly185Arg	missense_variant	2/2	ENST00000304661.6	NP_001011551.1
C1GALT1C1	NM_152692.5	c.553G>A	p.Gly185Arg	missense_variant	3/3		NP_689905.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
C1GALT1C1	ENST00000304661.6	c.553G>A	p.Gly185Arg	missense_variant	2/2	1	NM_001011551.3	ENSP00000304364.5
C1GALT1C1	ENST00000371313.2	c.553G>A	p.Gly185Arg	missense_variant	3/3	1		ENSP00000360363.2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Oct 10, 2024

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0102 - Loss of function is a likely mechanism of disease in this gene and is associated with haemolytic uremic syndrome, atypical, 8, with rhizomelic short stature (MIM#301110). This assertion is currently based on functional studies for only one missense variant (PMID: 37216524). (I) 0110 - This gene is associated with X-linked disease. Heterozygous females with skewed X-inactivation have been reported with an attenuated form of atypical haemolytic anaemia (PMID: 37216524). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to arginine. (I) 0253 - This variant is hemizygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.47	T;T
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.86	.;D
M_CAP	Benign	0.070	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Benign	-0.59	T
MutationAssessor	Uncertain	2.9	M;M
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-2.7	D;D
REVEL	Uncertain	0.48
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.012	D;D
Polyphen		1.0	D;D
Vest4		0.76
MutPred		0.92		Gain of methylation at G185 (P = 0.057);Gain of methylation at G185 (P = 0.057);
MVP		0.69
MPC		1.1
ClinPred		0.99	D
GERP RS		4.4
Varity_R		0.69
gMVP		0.96

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-119760469;