ClinVar Genomic variation as it relates to human health

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)

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.

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.

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.

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.

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.