NM_024079.5:c.535C>T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_024079.5(ALG8):c.535C>T(p.Arg179*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000355 in 1,606,700 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 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000036 ( 0 hom. )

Consequence

ALG8
NM_024079.5 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 2.13

Publications

4 publications found

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 Gene-Disease associations (from GenCC):

ALG8-congenital disorder of glycosylation
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: PanelApp Australia, G2P, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
polycystic liver disease 3 with or without kidney cysts
Inheritance: AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp

ALG8 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PVS1

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

PP5

Variant 11-78119193-G-A is Pathogenic according to our data. Variant chr11-78119193-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 492977.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.535C>T	p.Arg179*	stop_gained	Exon 5 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.535C>T	p.Arg179*	stop_gained	Exon 5 of 13	1	NM_024079.5	ENSP00000299626.5		Q9BVK2-1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

151966

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000239

AC:

AN:

250972

AF XY:

0.0000147

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000441

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000357

AC:

AN:

1454734

Hom.:

Cov.:

AF XY:

0.0000345

AC XY:

AN XY:

724102

show subpopulations

African (AFR)

AF:

0.0000300

AC:

AN:

33336

American (AMR)

AF:

0.00

AC:

AN:

44688

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26094

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39572

South Asian (SAS)

AF:

0.00

AC:

AN:

86100

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53372

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5742

European-Non Finnish (NFE)

AF:

0.0000425

AC:

AN:

1105724

Other (OTH)

AF:

0.0000499

AC:

AN:

60106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.429

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000329

AC:

AN:

151966

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74224

show subpopulations

African (AFR)

AF:

0.0000242

AC:

AN:

41378

American (AMR)

AF:

0.00

AC:

AN:

15242

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10548

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68014

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000579

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Polycystic liver disease 3 with or without kidney cysts

Pathogenic:2

Feb 21, 2018

OMIM

Significance:Pathogenic

Review Status:flagged submission

Collection Method:literature only

- -

Neuberg Centre For Genomic Medicine, NCGM

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The stop gained p.R179* in ALG8 (NM_024079.5) has been previously reported in heterozygous state in patients with polycystic liver disease (Besse W et al,2017). It has been submitted to ClinVar as Pathogenic based on the same. The p.R179* variant is observed in 1/16,224 (0.0062%) alleles from individuals of African background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant is predicted to cause loss of normal protein function through protein truncation. For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:2

Jan 15, 2025

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31589614, 36574950, 28375157) -

Apr 18, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PP2, PVS1 -

ALG8-related disorder

Pathogenic:2

Dec 22, 2023

PreventionGenetics, part of Exact Sciences

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The ALG8 c.535C>T variant is predicted to result in premature protein termination (p.Arg179*). This variant was firstly reported in the heterozygous state in a polycystic liver disease (PLD) patient who also has kidney cysts (Besse et al. 2017. PubMed ID: 28375157). In a later study of assessing the relationship between truncating ALG8 variants and polycystic kidney disease (PKD), individuals who are heterozygous for ALG8 pathogenic or likely pathogenic variants, including this variant, were shown to have increased risk of a mild (atypical) cystic kidney disease phenotype on imaging (Apple et al. 2023. PubMed ID: 36574950). Of note, the majority of loss-of-function variants in ALG8 have been reported in association with autosomal recessive congenital disorder of glycosylation (Human Gene Mutation Database). This variant is reported in 7 of 282,326 alleles in the gnomAD database. Nonsense variants in ALG8 are expected to be pathogenic. This variant is interpreted as likely pathogenic for autosomal recessive ALG8-related disorders. For autosomal dominant polycystic kidney-spectrum phenotype, however, it is currently uncertain since there is limited evidence to support the gene-disease relationship (ALG8 at https://www.clinicalgenome.org/). -

Dec 22, 2023

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PVS1, PS3_Moderate -

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

Pathogenic:1

Apr 20, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

ALG8 congenital disorder of glycosylation

Pathogenic:1

Jan 30, 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.Arg179*) 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 (rs762811727, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with kidney and/or liver cysts (PMID: 28375157, 36574950). ClinVar contains an entry for this variant (Variation ID: 492977). For these reasons, this variant has been classified as Pathogenic. -

Familial cystic renal disease

Pathogenic:1

Jun 01, 2025

Mayo Translational Polycystic Kidney Disease Center, Mayo Clinic

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

The c.535C>T variant results in a premature stop codon at position 179 (p.Arg179Ter) in the ALG8 gene.This nonsense mutation is predicted to cause loss of normal protein function either through truncated protein product, fulfilling the PVS1 criterion. The variant is extremely rare, with an allele frequency of <0.01% in gnomAD v4.1.0, supporting PM2. Clinically, it has been identified in four unrelated individuals with combined polycystic liver and kidney disease, a phenotype consistent with ALG8-related disease, providing evidence for PP4 (Jawaid, 2025). Given the nature of the mutation, its rarity in population databases, and its consistent presence in affected individuals, the variant is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Pathogenic

0.63

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

0.94

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Uncertain

0.92

PhyloP100

2.1

Vest4

0.94

GERP RS

4.7

Mutation Taster

=5/195

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over