ClinVar Miner

Submissions for variant NM_018389.4(SLC35C1):c.503_505del (p.Phe168del) (rs587777655)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000133551 SCV000245661 likely pathogenic Congenital disorder of glycosylation type 2C 2014-09-18 criteria provided, single submitter 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.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000513734 SCV000331279 uncertain significance not provided 2015-09-23 criteria provided, single submitter clinical testing
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000513734 SCV000609671 uncertain significance not provided 2017-05-30 criteria provided, single submitter clinical testing
GeneDx RCV000513734 SCV000709992 likely pathogenic not provided 2018-11-02 criteria provided, single submitter clinical testing The c.503_505delTCT variant, reported as c.501_503delCTT due to use of alternative nomenclature, has been observed with a pathogenic variant on the opposite allele (in trans) in in two siblings with global developmental delay, short stature, and dysmorphic facial features (Dauber et al., 2014). The c.503_505delTCT variant is observed in 85/126,402 (0.07%) alleles from individuals of European background, including a homozygous individual in large population cohorts (Lek et al., 2016). The c.503_505delTCT variant results in an in-frame deletion of a single Phenylalanine residue, denoted p.Phe168del. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Illumina Clinical Services Laboratory,Illumina RCV000133551 SCV000914511 uncertain significance Congenital disorder of glycosylation type 2C 2017-08-31 criteria provided, single submitter clinical testing 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.
Invitae RCV000133551 SCV000946765 uncertain significance Congenital disorder of glycosylation type 2C 2018-09-25 criteria provided, single submitter clinical testing This variant, c.503_505delTCT, results in the deletion of 1 amino acid of the SLC35C1 protein (p.Phe168del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs766692448, ExAC 0.05%), including at least one homozygous and/or hemizygous individual. This variant has been observed to segregate with congenital disorder of fucosylation type 2c (LADII) in a family, and was observed on the opposite chromosome (in trans) from a different pathogenic variant in individuals in that family (PMID: 23806237, 24403049). This variant is also known as p.Phe168del (c.501_503delCTT) and c.503_505delTCT in the literature. ClinVar contains an entry for this variant (Variation ID: 144046). Experimental studies have shown that this sequence change disrupts normal SLC35C1 protein function (PMID: 24403049). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
OMIM RCV000133551 SCV000188626 pathogenic Congenital disorder of glycosylation type 2C 2014-06-01 no assertion criteria provided literature only

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