rs376161880

chr11-78106895-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_024079.5(ALG8):c.1090C>T(p.Arg364Ter) 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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:17
• Conservation: PhyloP100: 6.76

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]

ACMG classification

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/exons	MANE	UniProt
ALG8	NM_024079.5	c.1090C>T	p.Arg364Ter	stop_gained	10/13	ENST00000299626.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALG8	ENST00000299626.10	c.1090C>T	p.Arg364Ter	stop_gained	10/13	1	NM_024079.5	P3

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152108 Hom.: 0 Cov.: 32

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: 14 AN: 251398 Hom.: 0 AF XY: 0.0000515 AC XY: 7 AN XY: 135870

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.: 0 Cov.: 31 AF XY: 0.0000756 AC XY: 55 AN XY: 727218

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: 14 AN: 152226 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74426

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.: 0

Bravo AF: 0.000110

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000412 AC: 5

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:17

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:8

Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	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 laboratory’s criteria to be classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 06, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 16, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 27, 2023	Observed in the heterozygous state in multiple unrelated individuals with polycystic liver disease (Besse et al., 2017); 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: 25525159, 26066342, 22306853, 34426522, 31589614, 19688606, 28375157) -

Polycystic liver disease 3 with or without kidney cysts Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Arkana Molecular Diagnostic Laboratory, Arkana Laboratories	Mar 23, 2020	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	Oct 09, 2023	- -

ALG8 congenital disorder of glycosylation Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 15, 2023	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). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jun 30, 2021

- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 18, 2020

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

Pathogenic, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Mar 11, 2021

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

Autosomal dominant polycystic liver disease Pathogenic:1

Pathogenic, no assertion criteria provided

research

Laboratory of Gastroenterology and Hepatology, Radboud University Medical Center

Jun 08, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.63
Cadd	Pathogenic	48
Dann	Uncertain	1.0
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.98	D
MutationTaster	Benign	1.0	A;A
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

Other links and lift over

dbSNP: rs376161880; hg19: chr11-77817941;