rs28939378

Positions:

chr16-5078789-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PP5_Very_Strong

The NM_019109.5(ALG1):c.773C>T(p.Ser258Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000604 in 1,612,744 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. S258S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00063 ( 0 hom. )

Consequence

ALG1
NM_019109.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:20O:1

Conservation

PhyloP100: 7.02

Variant links:

Genes affected

ALG1 (HGNC:18294): (ALG1 chitobiosyldiphosphodolichol beta-mannosyltransferase) The enzyme encoded by this gene catalyzes the first mannosylation step in the biosynthesis of lipid-linked oligosaccharides. This gene is mutated in congenital disorder of glycosylation type Ik. [provided by RefSeq, Dec 2008]

ALG1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM1

In a compositionally_biased_region Basic and acidic residues (size 14) in uniprot entity ALG1_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_019109.5

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 16-5078789-C-T is Pathogenic according to our data. Variant chr16-5078789-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4724.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-5078789-C-T is described in Lovd as [Pathogenic]. Variant chr16-5078789-C-T is described in Lovd as [Likely_pathogenic]. Variant chr16-5078789-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
ALG1	NM_019109.5 linkuse as main transcript	c.773C>T	p.Ser258Leu	missense_variant	7/13	ENST00000262374.10
ALG1	NM_001330504.2 linkuse as main transcript	c.440C>T	p.Ser147Leu	missense_variant	7/13
ALG1	XM_017023457.3 linkuse as main transcript	c.773C>T	p.Ser258Leu	missense_variant	7/12
ALG1	XR_007064892.1 linkuse as main transcript	n.780C>T		non_coding_transcript_exon_variant	7/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALG1	ENST00000262374.10 linkuse as main transcript	c.773C>T	p.Ser258Leu	missense_variant	7/13	1	NM_019109.5	P1	Q9BT22-1

Frequencies

GnomAD3 genomes

AF:

0.000329

AC:

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.000588

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000304

AC:

AN:

250018

Hom.:

AF XY:

0.000332

AC XY:

AN XY:

135558

show subpopulations

Gnomad AFR exome

AF:

0.000127

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000277

Gnomad NFE exome

AF:

0.000540

Gnomad OTH exome

AF:

0.000492

GnomAD4 exome

AF:

0.000633

AC:

924

AN:

1460556

Hom.:

Cov.:

AF XY:

0.000651

AC XY:

473

AN XY:

726582

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.0000895

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.000131

Gnomad4 NFE exome

AF:

0.000798

Gnomad4 OTH exome

AF:

0.000382

GnomAD4 genome

AF:

0.000329

AC:

AN:

152188

Hom.:

Cov.:

AF XY:

0.000229

AC XY:

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.000169

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.000588

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000407

Hom.:

Bravo

AF:

0.000351

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000228

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000280

AC:

EpiCase

AF:

0.000382

EpiControl

AF:

0.000771

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:20Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

ALG1-congenital disorder of glycosylation

Pathogenic:12

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 23, 2019	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2004	- -
Likely pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Feb 09, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Sep 02, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with congenital disorder of glycosylation, type Ik (MIM#608540). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from serine to leucine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (87 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported as homozygous or compound heterozygous in many individuals with type I congenital disorder of glycosylation (PMID: 26931382). It has also been reported as likely pathogenic/pathogenic many times in ClinVar. (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 03, 2022	Variant summary: ALG1 c.773C>T (p.Ser258Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0003 in 250018 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in ALG1 causing Congenital Disorder Of Glycosylation Type 1K (0.0003 vs 0.0011), allowing no conclusion about variant significance. c.773C>T has been reported in the literature in multiple individuals affected with Congenital Disorder Of Glycosylation Type 1K both in the homozygous and compound heterozygous state (Han_2020, Kranz_2004, Ng_2016). Functional studies have shown the variant to disrupt normal ALG1 enzymatic function (eg. Kranz_2004). 12 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	3billion	Sep 01, 2022	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.031%). The variant is in trans with NM_019109.5:c.826C>T. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.61; 3Cnet: 0.25). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000004724). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 258 of the ALG1 protein (p.Ser258Leu). This variant is present in population databases (rs28939378, gnomAD 0.05%). This missense change has been observed in individuals with congenital disorder of glycosylation (PMID: 14709599, 14973778, 14973782, 20679665, 22966035, 26931382, 27172925, 27325525, 28554332). ClinVar contains an entry for this variant (Variation ID: 4724). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ALG1 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects ALG1 function (PMID: 14973778, 22966035, 26931382). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	-	This variant has been previously reported as a compound heterozygous and homozygous change in patients with Congenital disorder of glycosylation, type Ik (PMID: 14709599, 27325525, 26931382), and as a compound heterozygous change in patients with seizure disorders (PMID: 28554332, 31618474). This variant could not rescue growth in an alg-1 deficient yeast strain, suggesting that the variant affects protein function (PMID: 14709599, 26931382). It is present in the heterozygous state in the gnomAD population database at a frequency of .03% (87/281390) and thus is presumed to be rare. The c.773C>T (p.Ser258Leu) variant is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.773C>T (p.Ser258Leu) variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	May 31, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 17, 2023	The ALG1 c.773C>T; p.Ser258Leu variant (rs28939378) is reported in the literature in the compound heterozygous or homozygous state in individuals affected with congenital disorders of glycosylation (Barba 2016, Bell 2011, Bowling 2017, Grubenmann 2004, Han 2020, Harshman 2016, Kranz 2004, Lipinski 2021, Ng 2016, Schwarz 2004). Functional analyses demonstrate reduced enzyme function (Grubenmann 2004, Kranz 2004, Ng 2016, Schwarz 2004). This variant is also reported in ClinVar (Variation ID: 4724), and is found in the general population with an overall allele frequency of 0.031% (87/281390 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.615). Based on available information, this variant is considered to be pathogenic. References: Barba C et al. Congenital disorders of glycosylation presenting as epileptic encephalopathy with migrating partial seizures in infancy. Dev Med Child Neurol. 2016 Oct;58(10):1085-91. PMID: 27172925. Bell CJ et al. Carrier testing for severe childhood recessive diseases by next-generation sequencing. Sci Transl Med. 2011 Jan 12;3(65):65ra4. PMID: 21228398. Bowling KM et al. Genomic diagnosis for children with intellectual disability and/or developmental delay. Genome Med. 2017 May 30;9(1):43. PMID: 28554332. Grubenmann CE et al. Deficiency of the first mannosylation step in the N-glycosylation pathway causes congenital disorder of glycosylation type Ik. Hum Mol Genet. 2004 Mar 1;13(5):535-42. PMID: 14709599. Han J et al. Rapid prenatal diagnosis of skeletal dysplasia using medical trio exome sequencing: Benefit for prenatal counseling and pregnancy management. Prenat Diagn. 2020 Apr;40(5):577-584. PMID: 31994750. Harshman LA et al. Congenital nephrotic syndrome in an infant with ALG1-congenital disorder of glycosylation. Pediatr Int. 2016 Aug;58(8):785-8. PMID: 27325525. Kranz C et al. Congenital disorder of glycosylation type Ik (CDG-Ik): a defect of mannosyltransferase I. Am J Hum Genet. 2004 Mar;74(3):545-51. PMID: 14973782. Lipinski P et al. Congenital disorders of glycosylation: Prevalence, incidence and mutational spectrum in the Polish population. Mol Genet Metab Rep. 2021 Feb 11;27:100726. PMID: 33643843. Ng BG et al. ALG1-CDG: Clinical and Molecular Characterization of 39 Unreported Patients. Hum Mutat. 2016 Jul;37(7):653-60. PMID: 26931382. Schwarz M et al. Deficiency of GDP-Man:GlcNAc2-PP-dolichol mannosyltransferase causes congenital disorder of glycosylation type Ik. Am J Hum Genet. 2004 Mar;74(3):472-81. PMID: 14973778. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Jul 28, 2017	- -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 28, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Nov 07, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 28, 2021	Published functional studies demonstrate a damaging effect (Grubenmann et al., 2004); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21228398, 14709599, 26931382, 14973782, 27325525, 28554332, 30609409, 31618474, 31994750, 32573669) -

Congenital disorder of glycosylation

Pathogenic:2

Likely pathogenic, no assertion criteria provided	research	University of Washington Center for Mendelian Genomics, University of Washington	May 25, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 26, 2017	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. -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 14, 2022

The c.773C>T (p.S258L) alteration is located in exon 7 (coding exon 7) of the ALG1 gene. This alteration results from a C to T substitution at nucleotide position 773, causing the serine (S) at amino acid position 258 to be replaced by a leucine (L). Based on data from gnomAD, the T allele has an overall frequency of 0.03% (87/281390) total alleles studied. The highest observed frequency was 0.05% (68/128302) of European (non-Finnish) alleles. This alteration was detected in the homozygous state and in conjunction with another alteration in ALG1 in multiple individuals with ALG1-related congenital disorder of glycosylation (Grubenmann, 2004; Kranz, 2004; Schwarz, 2004; Dupre, 2010; Morava, 2012; Barba, 2016; Ng, 2016; Han, 2020). This amino acid position is well conserved in available vertebrate species. Functional assays in yeast and patient-derived fibroblasts show <10% enzymatic activity in the biosynthesis of lipid-linked oligosaccharides (Kranz, 2004; Schwarz, 2004; Grubenmann, 2004; Dupre, 2010). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. -

Finnish congenital nephrotic syndrome

Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

University of Washington Center for Mendelian Genomics, University of Washington

Jun 21, 2016

- -

Encephalopathy

Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

- -

ALG12-congenital disorder of glycosylation

Other:1

not provided, no classification provided

phenotyping only

GenomeConnect - Invitae Patient Insights Network

Variant interpreted as Pathogenic and reported on 01-08-2021 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.43

BayesDel_addAF

Uncertain

0.083

BayesDel_noAF

Pathogenic

0.23

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.33

.;T;T;.

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

.;D;D;D

M_CAP

Uncertain

0.087

MetaRNN

Uncertain

0.68

D;D;D;D

MetaSVM

Uncertain

0.13

MutationAssessor

Uncertain

2.8

.;M;.;.

MutationTaster

Benign

1.0

A;A;A

PrimateAI

Benign

0.47

PROVEAN

Uncertain

-2.9

.;D;.;D

REVEL

Uncertain

0.61

Sift

Uncertain

0.0020

.;D;.;D

Sift4G

Uncertain

0.046

D;T;D;D

Polyphen

0.96

.;D;.;.

Vest4

0.62

MVP

0.95

MPC

0.18

ClinPred

0.44

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.27

gMVP

0.72

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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