11-45806301-CCTT-C

Position:

chr11-45806301-CCTT-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PM4_SupportingPP5

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

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:9U:3

Conservation

PhyloP100: 5.03

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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: {Uncertain_significance=3, Pathogenic=4, Likely_pathogenic=3}. Variant chr11-45806301-CCTT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC35C1	NM_018389.5 linkuse as main transcript	c.503_505delTCT	p.Phe168del	disruptive_inframe_deletion	1/2	ENST00000314134.4	NP_060859.4	Q96A29-1B3KQH0
SLC35C1	NM_001145265.2 linkuse as main transcript	c.464_466delTCT	p.Phe155del	disruptive_inframe_deletion	2/3		NP_001138737.1	Q96A29-2
SLC35C1	NM_001145266.1 linkuse as main transcript	c.464_466delTCT	p.Phe155del	disruptive_inframe_deletion	2/3		NP_001138738.1	Q96A29-2
SLC35C1	XM_011520203.4 linkuse as main transcript	c.503_505delTCT	p.Phe168del	disruptive_inframe_deletion	1/2		XP_011518505.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SLC35C1	ENST00000314134.4 linkuse as main transcript	c.503_505delTCT	p.Phe168del	disruptive_inframe_deletion	1/2	1	NM_018389.5	ENSP00000313318.3	Q96A29-1
SLC35C1	ENST00000442528.2 linkuse as main transcript	c.464_466delTCT	p.Phe155del	disruptive_inframe_deletion	2/3	1		ENSP00000412408.2	Q96A29-2
SLC35C1	ENST00000526817.2 linkuse as main transcript	c.464_466delTCT	p.Phe155del	disruptive_inframe_deletion	2/3	2		ENSP00000432145.2	Q96A29-2E9PS26
SLC35C1	ENST00000530471.1 linkuse as main transcript	c.464_466delTCT	p.Phe155del	disruptive_inframe_deletion	2/2	3		ENSP00000432669.1	E9PPI4

Frequencies

GnomAD3 genomes

AF:

0.000453

AC:

AN:

152232

Hom.:

Cov.:

show subpopulations

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:

AN:

250286

Hom.:

AF XY:

0.000340

AC XY:

AN XY:

135464

show subpopulations

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.:

AF XY:

0.000679

AC XY:

493

AN XY:

726584

show subpopulations

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:

AN:

152232

Hom.:

Cov.:

AF XY:

0.000417

AC XY:

AN XY:

74370

show subpopulations

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.:

Bravo

AF:

0.000423

EpiCase

AF:

0.000763

EpiControl

AF:

0.000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:9Uncertain:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Leukocyte adhesion deficiency type II

Pathogenic:6Uncertain:1

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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2014	- -
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, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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. -
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. -
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. -

not provided

Pathogenic:2Uncertain:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 15, 2024	In-frame deletion of 1 amino acid 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) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 23, 2015	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 30, 2017	- -

SLC35C1-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 20, 2024

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over