rs28939087

Positions:

• chr11-45806240-C-T

Variant summary

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

The ENST00000314134.4(SLC35C1):​c.439C>T​(p.Arg147Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,456,298 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R147H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SLC35C1 ENST00000314134.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 4.91

Genes affected

SLC35C1 (HGNC:20197): (solute carrier family 35 member C1) This gene encodes a GDP-fucose transporter that is found in the Golgi apparatus. Mutations in this gene result in congenital disorder of glycosylation type IIc. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 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, 0.971
• PP5: Variant 11-45806240-C-T is Pathogenic according to our data. Variant chr11-45806240-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4739.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-45806240-C-T is described in Lovd as [Pathogenic]. Variant chr11-45806240-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC35C1	NM_018389.5	c.439C>T	p.Arg147Cys	missense_variant	1/2	ENST00000314134.4	NP_060859.4
SLC35C1	NM_001145265.2	c.400C>T	p.Arg134Cys	missense_variant	2/3		NP_001138737.1
SLC35C1	NM_001145266.1	c.400C>T	p.Arg134Cys	missense_variant	2/3		NP_001138738.1
SLC35C1	XM_011520203.4	c.439C>T	p.Arg147Cys	missense_variant	1/2		XP_011518505.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC35C1	ENST00000314134.4	c.439C>T	p.Arg147Cys	missense_variant	1/2	1	NM_018389.5	ENSP00000313318	P4
SLC35C1	ENST00000442528.2	c.400C>T	p.Arg134Cys	missense_variant	2/3	1		ENSP00000412408	A1
SLC35C1	ENST00000526817.2	c.400C>T	p.Arg134Cys	missense_variant	2/3	2		ENSP00000432145	A1
SLC35C1	ENST00000530471.1	c.400C>T	p.Arg134Cys	missense_variant	2/2	3		ENSP00000432669

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1456298 Hom.: 0 Cov.: 35 AF XY: 0.00000276 AC XY: 2 AN XY: 724696

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Leukocyte adhesion deficiency type II Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 15, 2021	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change affects SLC35C1 function (PMID: 11326279, 11326280, 16455955). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 4739). This missense change has been observed in individual(s) with congenital disorder of glycosylation (PMID: 11326279, 11326280). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with cysteine at codon 147 of the SLC35C1 protein (p.Arg147Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2001	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.78	.;D;T
Eigen	Pathogenic	0.76
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Uncertain	-0.0068	T
MutationAssessor	Pathogenic	3.5	.;M;.
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-7.7	D;D;D
REVEL	Pathogenic	0.70
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.91
MutPred		0.93		.;Loss of methylation at R147 (P = 0.0124);.;
MVP		0.84
MPC		1.8
ClinPred		1.0	D
GERP RS		3.7
Varity_R		0.96
gMVP		0.75

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: rs28939087; hg19: chr11-45827791; COSMIC: COSV58480071; COSMIC: COSV58480071;