ClinVar Miner

Submissions for variant NM_019109.4(ALG1):c.773C>T (p.Ser258Leu) (rs28939378)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 12
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000210565 SCV000262918 pathogenic Inborn genetic diseases 2014-02-06 criteria provided, single submitter clinical testing
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000081987 SCV000511284 pathogenic not provided 2016-11-07 criteria provided, single submitter clinical testing
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000004989 SCV000745150 pathogenic Congenital disorder of glycosylation type 1K 2017-05-31 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000081987 SCV000232284 pathogenic not provided 2014-10-28 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000004989 SCV000893399 pathogenic Congenital disorder of glycosylation type 1K 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000081987 SCV000617787 pathogenic not provided 2018-12-10 criteria provided, single submitter clinical testing The S258L variant in the ALG1 gene is one of the most common variants identified in the ALG1 gene has been reported previously in several unrelated patients with congenital disorder of glycosylation type Ik who were homozygous for S258L or heterozygous for S258L and a second variant in the ALG1 gene. (Grubenemann et al., 2004). In vitro functional studies in S. cerevisiae yeast showed that expression of S258L did not enable alg1-1 yeast mutants to grow to the same extent as compared to the wild type protein, thus supporting the pathological impact of the variant (Grubenmann et al., 2004). In summary, we interpret S258L as a pathogenic variant.
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000004989 SCV000743746 likely pathogenic Congenital disorder of glycosylation type 1K 2017-07-28 criteria provided, single submitter clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000004989 SCV000265559 likely pathogenic Congenital disorder of glycosylation type 1K 2017-02-09 criteria provided, single submitter research
Invitae RCV000004989 SCV000932120 pathogenic Congenital disorder of glycosylation type 1K 2018-10-01 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 258 of the ALG1 protein (p.Ser258Leu). The serine residue is moderately conserved and there is a large physicochemical difference between serine and leucine. This variant is present in population databases (rs28939378, ExAC 0.04%). This variant has been observed in multiple individuals affected with congenital disorder of glycosylation as homozygous or in combination with another ALG1 variant (PMID: 26931382, 14709599, 27325525, 26931382, 28554332, 22966035, 20679665, 14973782, 14973778, 27172925). ClinVar contains an entry for this variant (Variation ID: 4724). Experimental studies have shown that this missense change disrupts normal ALG1 enzymatic function (PMID: 22966035, 14973778, 26931382). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000606536 SCV000731828 pathogenic Congenital disorder of glycosylation 2017-09-26 criteria provided, single submitter clinical testing The p.Ser258Leu variant in ALG1 has been reported in at least 10 homozygous and 14 compound heterozygous individuals with a congenital disorder of glycosylation (Grubenmann 2004, Schwarz 2004, Kranz 2004, Harshman 2016, Ng 2016, Park 2016, Barba 2016, and Bowling 2017), and has also been reported in ClinVar (Variation ID#4724). In vitro functional studies provide evidence that the p.Ser258ZLeu var iant impacts the protein (Grubenmann 2004, Schwarz 2004, Kranz 2004, and Ng 2016 ). This variant has been identified in 0.05% (67/126078) of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; d bSNP rs28939378). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency . In summary, although additional studies are required to fully establish its c linical significance, the p.Ser258Leu variant is pathogenic for congenital disor ders of glycosylation in an autosomal recessive manner based on functional studi es and its occurrence in individuals with this disease.
OMIM RCV000004989 SCV000025165 pathogenic Congenital disorder of glycosylation type 1K 2004-03-01 no assertion criteria provided literature only
University of Washington Center for Mendelian Genomics,University of Washington RCV000655875 SCV000748668 likely pathogenic Finnish congenital nephrotic syndrome 2016-06-21 no assertion criteria provided research

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.