rs376161880

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_024079.5(ALG8):c.1090C>T(p.Arg364*) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000824 in 1,614,060 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000081 ( 0 hom. )

Consequence

ALG8
NM_024079.5 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:21

Conservation

PhyloP100: 6.76

Variant links:

Genes affected

ALG8 (HGNC:23161): (ALG8 alpha-1,3-glucosyltransferase) This gene encodes a member of the ALG6/ALG8 glucosyltransferase family. The encoded protein catalyzes the addition of the second glucose residue to the lipid-linked oligosaccharide precursor for N-linked glycosylation of proteins. Mutations in this gene have been associated with congenital disorder of glycosylation type Ih (CDG-Ih). Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

ALG8 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 11-78106895-G-A is Pathogenic according to our data. Variant chr11-78106895-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 280116.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALG8	NM_024079.5 link	c.1090C>T	p.Arg364*	stop_gained	Exon 10 of 13	ENST00000299626.10	NP_076984.2	Q9BVK2-1A0A024R5K5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALG8	ENST00000299626.10 link	c.1090C>T	p.Arg364*	stop_gained	Exon 10 of 13	1	NM_024079.5	ENSP00000299626.5		Q9BVK2-1

Frequencies

GnomAD3 genomes

AF:

0.0000920

AC:

AN:

152108

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.000958

GnomAD3 exomes

AF:

0.0000557

AC:

AN:

251398

Hom.:

AF XY:

0.0000515

AC XY:

AN XY:

135870

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000814

AC:

119

AN:

1461834

Hom.:

Cov.:

AF XY:

0.0000756

AC XY:

AN XY:

727218

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000962

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.0000920

AC:

AN:

152226

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74426

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.000948

Alfa

AF:

0.000194

Hom.:

Bravo

AF:

0.000110

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000412

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:21

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:9

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 07, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed in the heterozygous state in multiple unrelated individuals with polycystic liver disease (PMID: 28375157); Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25525159, 26066342, 22306853, 34426522, 31589614, 28375157, 36574950, 36938085, 37628703, 19688606) -

Dec 06, 2019

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ALG8 p.R364* variant was identified as a heterozygous variant in 3 of 102 individuals (frequency: 0.015) with polycystic liver disease (Besse_2017_PMID:28375157). In the compound heterozygous state, the variant has been reported in cases with congenital disorders of glycosylation Ih in probands who carried another pathogenic ALG8 variant (Vesela_2009_PMID:19688606; Hock_2015_PMID:26066342). The variant was identified in dbSNP (ID: rs376161880) and ClinVar (classified as pathogenic by GeneDx and EGL Genetics). The variant was identified in control databases in 18 of 282788 chromosomes at a frequency of 0.00006365 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 14 of 129120 chromosomes (freq: 0.000108), South Asian in 2 of 30616 chromosomes (freq: 0.000065), African in 1 of 24954 chromosomes (freq: 0.00004) and Latino in 1 of 35436 chromosomes (freq: 0.000028), but was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), or Other populations. The c.1090C>T variant leads to a premature stop codon at position 364 which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the ALG8 gene are an established mechanism of disease in congenital disorders of glycosylation Ih and are the type of variant expected to cause the disorder when found in the homozygous or compound heterozygous state. Loss of function variants in the ALG8 gene may also contribute to autosomal dominant polycystic liver disease. In summary, based on the above information this variant meets our laboratoryâ€šÃ„Ã´s criteria to be classified as pathogenic. -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 16, 2017

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 09, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ALG8 c.1090C>T; p.Arg364Ter variant (rs376161880, ClinVar Variation ID: 280116) is reported heterozygous in individuals with polycystic liver disease and compound heterozygous in individuals with congenital disorder of glycosylation (Albokhari 2022, Apple 2023, Boerrigter 2023, Vesela 2009). This variant is found in the non-Finnish European population with an allele frequency of 0.01% (14/129120 alleles) in the Genome Aggregation Database (v.2.1.1). This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Albokhari D et al. ALG8-CDG: Molecular and phenotypic expansion suggests clinical management guidelines. J Inherit Metab Dis. 2022 Sep;45(5):969-980. PMID: 35716054. Apple B et al. Individuals heterozygous for ALG8 protein-truncating variants are at increased risk of a mild cystic kidney disease. Kidney Int. 2023 Mar;103(3):607-615. PMID: 36574950. Boerrigter MM et al. Novel a-1,3-Glucosyltransferase Variants and Their Broad Clinical Polycystic Liver Disease Spectrum. Genes (Basel). 2023 Aug 19;14(8):1652. PMID: 37628703. Vesela K et al. A new case of ALG8 deficiency (CDG Ih). J Inherit Metab Dis. 2009 Dec;32 Suppl 1. PMID: 19688606. -

Polycystic liver disease 3 with or without kidney cysts

Pathogenic:5

Mar 23, 2020

Arkana Molecular Diagnostic Laboratory, Arkana Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 06, 2021

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 Ih (MIM#608104) and polycystic liver disease 3 with or without kidney cysts (MIM#617874). (I) 0108 - This gene is associated with both recessive and dominant disease, where the same variants have been reported to cause both conditions (PMID: 28375157; PMID: 26066342). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a condition (18 heterozygotes, 0 homozygotes). (SP) 0702 - Other NMD-predicted variants comparable to the one identified in this case have strong previous evidence for pathogenicity. These variants have been reported in compound heterozygous patients with congenital disorder of glycosylation (CDG) and heterozygous patients with polycystic liver disease (PLD) (Decipher, ClinVar, PMID: 28375157, PMID: 26066342). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times as pathogenic, and observed in compound heterozygous patients with CDG and heterozygous patients with PLD and kidney cysts (ClinVar, PMID: 28375157, PMID: 26066342, PMID: 19688606). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Dec 22, 2023

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an allele frequency greater than expected for the associated disorder in the gnomAD v2.1.1 dataset and therefore considered benign. Predicted Consequence/Location: Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000280116 /PMID: 19688606). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Mar 01, 2022

OMIM

Significance: Pathogenic

Review Status: flagged submission

Collection Method: literature only

- -

Oct 09, 2023

Zotz-Klimas Genetics Lab, MVZ Zotz Klimas

Significance: Pathogenic

Review Status: flagged submission

Collection Method: clinical testing

- -

ALG8 congenital disorder of glycosylation

Pathogenic:2

Mar 01, 2022

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Nov 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg364*) in the ALG8 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ALG8 are known to be pathogenic (PMID: 19862844). This variant is present in population databases (rs376161880, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with congenital disorder of glycosylation type 1h (PMID: 19688606). ClinVar contains an entry for this variant (Variation ID: 280116). For these reasons, this variant has been classified as Pathogenic. -

ALG8 congenital disorder of glycosylation;C4693472:Polycystic liver disease 3 with or without kidney cysts

Pathogenic:1

Jun 30, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Pathogenic:1

Nov 18, 2020

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1090C>T (p.R364*) alteration, located in exon 10 (coding exon 10) of the ALG8 gene, consists of a C to T substitution at nucleotide position 1090. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 364. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from the Genome Aggregation Database (gnomAD) database, the ALG8 c.1090C>T alteration was observed in 0.01% (18/282788) of total alleles studied, with a frequency of 0.01% (14/129120) in the European (non-Finnish) subpopulation. This alteration has been detected with another mutation in patients with clinical and biochemical features consistent with congenital disorder of glycosylation type Ih, and parental testing confirmed in trans in one patient (Vesela, 2009; Höck, 2015). This alteration has also been detected in the heterozygous state in three unrelated patients with polycystic liver disease with or without renal cysts (Besse, 2017); however, this disease does not currently meet published gene-disease clinical validity criteria for this gene (Smith, 2017). Based on the available evidence, this alteration is classified as pathogenic. -

See cases

Pathogenic:1

Mar 11, 2021

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PVS1, PS4, PM2, PM3 -

Autosomal dominant polycystic liver disease

Pathogenic:1

Jun 08, 2021

Laboratory of Gastroenterology and Hepatology, Radboud University Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

ALG8-related disorder

Pathogenic:1

Jun 05, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ALG8 c.1090C>T variant is predicted to result in premature protein termination (p.Arg364*). This variant has been reported in the compound heterozygous state in multiple individuals with congenital disorder of glycosylation type 1h (Vesela et al. 2009. PubMed ID: 19688606; Höck et al. 2015. PubMed ID: 26066342). This variant has also been reported in the heterozygous state, without a second ALG8 variant, in individuals with polycystic liver disease (Besse et al. 2017. PubMed ID: 28375157); however, there have not yet been other studies to confirm this association. This variant is reported in 0.011% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Nonsense variants in ALG8 are expected to be pathogenic. We interpret this variant as pathogenic for autosomal recessive congenital disorder of glycosylation type 1h. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.48

BayesDel_noAF

Pathogenic

0.63

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.92

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Pathogenic

0.98

Vest4

0.90

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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