rs587777655

chr11-45806301-CCTT-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM4_Supporting PP5

The NM_018389.5(SLC35C1):c.503_505del(p.Phe168del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.000675 in 1,612,702 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S167S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00045 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00070 (1 hom.)
• Consequence: SLC35C1 NM_018389.5 inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:8 U:3
• Conservation: PhyloP100: 5.03

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_018389.5. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 11-45806301-CCTT-C is Pathogenic according to our data. Variant chr11-45806301-CCTT-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 144046.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Uncertain_significance=3, Pathogenic=4}. Variant chr11-45806301-CCTT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC35C1	NM_018389.5	c.503_505del	p.Phe168del	inframe_deletion	1/2	ENST00000314134.4
SLC35C1	NM_001145265.2	c.464_466del	p.Phe155del	inframe_deletion	2/3
SLC35C1	NM_001145266.1	c.464_466del	p.Phe155del	inframe_deletion	2/3
SLC35C1	XM_011520203.4	c.503_505del	p.Phe168del	inframe_deletion	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC35C1	ENST00000314134.4	c.503_505del	p.Phe168del	inframe_deletion	1/2	1	NM_018389.5	P4
SLC35C1	ENST00000442528.2	c.464_466del	p.Phe155del	inframe_deletion	2/3	1		A1
SLC35C1	ENST00000526817.2	c.464_466del	p.Phe155del	inframe_deletion	2/3	2		A1
SLC35C1	ENST00000530471.1	c.464_466del	p.Phe155del	inframe_deletion	2/2	3

Frequencies

GnomAD3 genomes AF: 0.000453 AC: 69 AN: 152232 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000970

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000320 AC: 80 AN: 250286 Hom.: 1 AF XY: 0.000340 AC XY: 46 AN XY: 135464

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000191

Gnomad NFE exome AF: 0.000644

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000698 AC: 1020 AN: 1460470 Hom.: 1 AF XY: 0.000679 AC XY: 493 AN XY: 726584

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000192

Gnomad4 NFE exome AF: 0.000893

Gnomad4 OTH exome AF: 0.000199

GnomAD4 genome AF: 0.000453 AC: 69 AN: 152232 Hom.: 0 Cov.: 32 AF XY: 0.000417 AC XY: 31 AN XY: 74370

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000970

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000608 Hom.: 0

Bravo AF: 0.000423

EpiCase AF: 0.000763

EpiControl AF: 0.000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:8 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Leukocyte adhesion deficiency type II Pathogenic:6 Uncertain:1

Pathogenic, criteria provided, single submitter	research	Bicknell laboratory, University of Otago	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 28, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2014	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 18, 2014	The Phe155del variant in SLC35C1 has been reported in 3 compound heterozygous individuals with clinical features of congenital disorder of glycosylation IIc (CDG IIc) and segregated with disease in 1 affected compound heterozygous relative (all affected individuals carried a nonsense variant on the other allele; Jones 2013, Dauber 2014). This variant has also been identified in 1/8250 of European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant is a deletion of a phenylalanine residue at position 155 and is not predicted to alter the protein reading-frame. It is unclear how this deletion will impact the protein. In summary, although additional studies are required to fully establish its clinical significance, the Phe155del variant is likely pathogenic, due to its occurrence in trans with a pathogenic variant in affected individuals. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 26, 2024	This variant, c.503_505del, results in the deletion of 1 amino acid(s) of the SLC35C1 protein (p.Phe168del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs766692448, gnomAD 0.07%), including at least one homozygous and/or hemizygous individual. This variant has been observed in individual(s) with clinical features of congenital disorder of fucosylation type 2c (PMID: 23806237, 24403049, 32313197). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as p.Phe168del (c.501_503delCTT) and c.503_505delTCT. ClinVar contains an entry for this variant (Variation ID: 144046). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects SLC35C1 function (PMID: 24403049). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 10, 2023	Variant summary: SLC35C1 c.503_505delTCT (p.Phe168del) results in an in-frame deletion that is predicted to remove one amino acid from the Sugar phosphate transporter domain (IPR004853) of the encoded protein. The variant allele was found at a frequency of 0.00032 in 250286 control chromosomes in the gnomAD database, including 1 homozygote (see discussed below). Due to an unknown prevalence of SLC35C1 associated congenital disorders of gycosylation/Leukocyte Adhesion Deficiency Type II, this frequency relative to that expected for a pathogenic variant in SLC35C1 is unknown allowing no conclusion about variant significance. c.503_505delTCT has been reported in the literature as a compound heterozygous genotype in extensively genotyped cohorts of individuals affected with features of Leukocyte Adhesion Deficiency Type II/SLC35C1-CDG/short stature/intellectual disability (example, Dauber_2014, Jones_2013, Knapp_2020, Starosta_2021). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating a variant specific impact on protein function has been reported. However, an analysis of the patients with the reported compound heterozygous genotypes did demonstrate a partial defect in fucosylation (example, Dauber_2014, Knapp_2020, Tahata). Furthermore, at-least one report of a patient with SLC35C1-CDG who responded to oral fucose supplementation with an improvement from a tendency to infections has been reported (example, Strosta_2021). Lastly, the possibility of this variant having a mildly deleterious effect on protein due to the presence of one homozygote in the gnomAD database has been suggested (Knapp_2020). The following publications have been ascertained in the context of this evaluation (PMID: 29030401, 24403049, 23806237, 32313197, 33413482, 35338746). Seven 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=3, likely pathogenic, n=2, pathogenic, n=2). Some submitters cite overlapping, but not all evidences utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic for mild to moderate leukocyte adhesion deficiency/SLC35C1-associated CDG amenable to fucose supplementation. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Aug 31, 2017	The SLC35C1 c.503_505delTCT (p.Phe168del) variant is an inframe deletion vaiant which has been reported in two studies in which it is identified in a compound heterozygous state with a stop-gained variant in at least two individuals with congenital disorders of glycosylation (Jones et al. 2013; Dauber et al. 2014). The individuals reported in Dauber et al. (2014) are brothers who are noted to have short stature and global developmental delay, features typical of congenital disorders of glycosylation, though the authors note that additional key features, including leukocytosis, recurrent infections, and Bombay blood type, were absent. Analysis of IgG heavy chain N-glycans as well as analysis of CD15 expression and adhesive interactions of granulocytes suggest the variants identified in the brothers altered function of the SLC35C1 gene product. Control data are unavailable for this variant, which is reported at a frequency of 0.000673 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the limited evidence, the p.Phe168del variant is classified a variant of unknown significance but suspicious for pathogenicity for congenital disorders of glycosylation. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

not provided Pathogenic:2 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 30, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 23, 2015	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 08, 2023	In-frame deletion of 1 amino acid in a non-repeat region; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 23891399, 32313197, 34389986, 35338746, 23806237, 24403049, 33144682, 29030401) -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2020	- -

Computational scores

Source: dbNSFP v4.3

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: rs587777655; hg19: chr11-45827852;