rs587777655

Variant names:

• chr11-45806301-CCTT-C
• rs587777655
• NM_018389.5:c.503_505delTCT

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM4_Supporting PP5 BS1_Supporting

The NM_018389.5(SLC35C1):​c.503_505delTCT​(p.Phe168del) variant causes a disruptive 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).

• Frequency:
  • Genomes: 𝑓 0.00045 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00070 (1 hom.)
• Consequence: SLC35C1 NM_018389.5 disruptive_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:10 U:2
• Conservation: PhyloP100: 5.03
• Publications: 4 publications found

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]

SLC35C1 Gene-Disease associations (from GenCC):

• leukocyte adhesion deficiency type II

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• 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 VariationId is 144046.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000453 (69/152232) while in subpopulation NFE AF = 0.00097 (66/68028). AF 95% confidence interval is 0.000782. There are 0 homozygotes in GnomAd4. There are 31 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC35C1	NM_018389.5	c.503_505delTCT	p.Phe168del	disruptive_inframe_deletion	Exon 1 of 2	ENST00000314134.4	NP_060859.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC35C1	ENST00000314134.4	c.503_505delTCT	p.Phe168del	disruptive_inframe_deletion	Exon 1 of 2	1	NM_018389.5	ENSP00000313318.3
SLC35C1	ENST00000442528.2	c.464_466delTCT	p.Phe155del	disruptive_inframe_deletion	Exon 2 of 3	1		ENSP00000412408.2
SLC35C1	ENST00000526817.2	c.464_466delTCT	p.Phe155del	disruptive_inframe_deletion	Exon 2 of 3	2		ENSP00000432145.2
SLC35C1	ENST00000530471.1	c.464_466delTCT	p.Phe155del	disruptive_inframe_deletion	Exon 2 of 2	3		ENSP00000432669.1

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

GnomAD2 exomes AF: 0.000320 AC: 80 AN: 250286 AF XY: 0.000340

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 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

African (AFR) AF: 0.000119 AC: 4 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.000192 AC: 10 AN: 52030

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000893 AC: 993 AN: 1112002

Other (OTH) AF: 0.000199 AC: 12 AN: 60384

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

African (AFR) AF: 0.0000482 AC: 2 AN: 41462

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000970 AC: 66 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2090

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:10 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Leukocyte adhesion deficiency type II Pathogenic:7

Oct 28, 2021

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 10, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Sep 18, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 gene product 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. -

-

Bicknell laboratory, University of Otago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Jun 01, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jan 01, 2024

Daryl Scott Lab, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS4, PM3, PM5 -

not provided Pathogenic:2 Uncertain:2

Nov 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 23, 2015

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 30, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

- -

Apr 27, 2025

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In-frame deletion of 1 amino acids in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23891399, 32313197, 34389986, 35338746, 23806237, 33144682, 29030401, 24403049, 38843991, 33413482) -

SLC35C1-related disorder Pathogenic:1

Sep 20, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The SLC35C1 c.503_505delTCT variant is predicted to result in an in-frame deletion (p.Phe168del). The c.503_505del variant has been reported in the compound heterozygous state in two individuals in a cohort referred for molecular testing for congenital disorders of glycosylation (CDG); however, detailed clinical information of these individuals was not provided (Jones et al. 2013. PubMed ID: 23806237). This variant has also been reported in the compound heterozygous state in individuals with short stature and intellectual disability, but without the characteristic immune deficiencies normally associated with SLC35C1-CDG (Dauber et al. 2014. PubMed ID: 24403049; Knapp et al. 2020. PubMed ID: 32313197). This variant is reported in 0.069% of alleles in individuals of European (Non-Finnish) descent in gnomAD, including one homozygous individual. It has been suggested that this variant may have a mildly deleterious effect on the protein (Knapp et al. 2020. PubMed ID: 32313197). This variant has conflicting interpretations in ClinVar regarding its pathogenicity, ranging from pathogenic to likely pathogenic to uncertain significance ( https://www.ncbi.nlm.nih.gov/clinvar/variation/144046/). Taken together, this variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.0
Mutation Taster		=56/44	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs587777655; hg19: chr11-45827852;