ClinVar Genomic variation as it relates to human health
NM_024079.5(ALG8):c.1090C>T (p.Arg364Ter)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_024079.5(ALG8):c.1090C>T (p.Arg364Ter)
Variation ID: 280116 Accession: VCV000280116.46
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11q14.1 11: 78106895 (GRCh38) [ NCBI UCSC ] 11: 77817941 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Dec 6, 2016 May 1, 2024 Oct 15, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_024079.5:c.1090C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_076984.2:p.Arg364Ter nonsense NM_001007027.3:c.1090C>T NP_001007028.1:p.Arg364Ter nonsense NC_000011.10:g.78106895G>A NC_000011.9:g.77817941G>A NG_008926.1:g.37759C>T - Protein change
- R364*
- Other names
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- Canonical SPDI
- NC_000011.10:78106894:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00004
The Genome Aggregation Database (gnomAD), exomes 0.00006
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
The Genome Aggregation Database (gnomAD) 0.00010
Trans-Omics for Precision Medicine (TOPMed) 0.00011
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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ALG8 | - | - |
GRCh38 GRCh37 |
326 | 339 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic/Likely pathogenic (8) |
criteria provided, multiple submitters, no conflicts
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Mar 27, 2023 | RCV000356855.22 | |
Pathogenic (3) |
criteria provided, single submitter
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Mar 23, 2020 | RCV000584794.13 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 30, 2021 | RCV001535890.10 | |
Pathogenic (2) |
criteria provided, single submitter
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Oct 15, 2023 | RCV001843038.10 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 11, 2021 | RCV002252077.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 18, 2020 | RCV002519040.9 | |
Pathogenic (1) |
no assertion criteria provided
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Jun 8, 2021 | RCV003448977.1 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Mar 16, 2017)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000705913.2
First in ClinVar: Apr 02, 2018 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Pathogenic
(Mar 23, 2020)
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criteria provided, single submitter
Method: clinical testing
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Polycystic liver disease 3 with or without kidney cysts
Affected status: yes
Allele origin:
inherited
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Arkana Molecular Diagnostic Laboratory, Arkana Laboratories
Accession: SCV001431566.1
First in ClinVar: Sep 14, 2020 Last updated: Sep 14, 2020
Comment:
NGS Exome with Sanger sequencing confirmation
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Number of individuals with the variant: 1
Secondary finding: no
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Pathogenic
(Jun 30, 2021)
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criteria provided, single submitter
Method: clinical testing
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ALG8 congenital disorder of glycosylation
Polycystic liver disease 3 with or without kidney cysts
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV001752520.1
First in ClinVar: Jul 18, 2021 Last updated: Jul 18, 2021
Comment:
This variant has been detected in individual(s) who were sent for testing of Renasight - kidney gene panel.
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Pathogenic
(Mar 11, 2021)
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criteria provided, single submitter
Method: clinical testing
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See cases
Affected status: yes
Allele origin:
germline
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Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV002523934.1
First in ClinVar: Jun 09, 2022 Last updated: Jun 09, 2022 |
Comment:
ACMG classification criteria: PVS1, PS4, PM2, PM3
Clinical Features:
Portal vein thrombosis (present) , Thrombophilia (present) , Failure to thrive (present) , Delayed speech and language development (present)
Geographic origin: Brazil
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Pathogenic
(Mar 27, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000329974.9
First in ClinVar: Dec 06, 2016 Last updated: Apr 01, 2023 |
Comment:
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 … (more)
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) (less)
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Likely pathogenic
(Dec 06, 2019)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002021350.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Oct 15, 2023)
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criteria provided, single submitter
Method: clinical testing
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ALG8 congenital disorder of glycosylation
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV003014213.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 20, 2024 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Nov 18, 2020)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV003757014.2
First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
unknown
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Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001553282.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001929260.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001954526.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV002035033.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021 |
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Likely pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV002036077.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021 |
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Pathogenic
(Mar 01, 2022)
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no assertion criteria provided
Method: literature only
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POLYCYSTIC LIVER DISEASE 3 WITH KIDNEY CYSTS
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000692485.3
First in ClinVar: Feb 25, 2018 Last updated: Mar 05, 2022 |
Comment on evidence:
Polycystic Liver Disease 3 with Kidney Cysts In 3 unrelated patients (YU313, T-55, and T-70) with polycystic liver disease-3 with kidney cysts (PCLD3; 617874), Besse … (more)
Polycystic Liver Disease 3 with Kidney Cysts In 3 unrelated patients (YU313, T-55, and T-70) with polycystic liver disease-3 with kidney cysts (PCLD3; 617874), Besse et al. (2017) identified a heterozygous c.1090C-T transition in the ALG8 gene, resulting in an arg364-to-ter (R364X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was present at a low frequency (4.5 x 10(-5)) in the ExAC database. Two patients were of European descent and 1 was of African American descent. No family data were available for segregation analysis. Functional studies of the variant and studies of patient cells were not performed. Congenital Disorder of Glycosylation, Type Ih For discussion of the c.1090C-T transition in the ALG8 gene, resulting in an R364X substitution, that was found in compound heterozygous state in a patient (patient 2) with congenital disorder of glycosylation type Ih (CDG1H; 608104) by Hock et al. (2015), see 608103.0004. (less)
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Pathogenic
(Mar 01, 2022)
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no assertion criteria provided
Method: literature only
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CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ih
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV002102402.1
First in ClinVar: Mar 05, 2022 Last updated: Mar 05, 2022 |
Comment on evidence:
Polycystic Liver Disease 3 with Kidney Cysts In 3 unrelated patients (YU313, T-55, and T-70) with polycystic liver disease-3 with kidney cysts (PCLD3; 617874), Besse … (more)
Polycystic Liver Disease 3 with Kidney Cysts In 3 unrelated patients (YU313, T-55, and T-70) with polycystic liver disease-3 with kidney cysts (PCLD3; 617874), Besse et al. (2017) identified a heterozygous c.1090C-T transition in the ALG8 gene, resulting in an arg364-to-ter (R364X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was present at a low frequency (4.5 x 10(-5)) in the ExAC database. Two patients were of European descent and 1 was of African American descent. No family data were available for segregation analysis. Functional studies of the variant and studies of patient cells were not performed. Congenital Disorder of Glycosylation, Type Ih For discussion of the c.1090C-T transition in the ALG8 gene, resulting in an R364X substitution, that was found in compound heterozygous state in a patient (patient 2) with congenital disorder of glycosylation type Ih (CDG1H; 608104) by Hock et al. (2015), see 608103.0004. (less)
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Pathogenic
(Jun 08, 2021)
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no assertion criteria provided
Method: research
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Isolated polycystic liver disease
Affected status: yes
Allele origin:
germline
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Laboratory of Gastroenterology and Hepatology, Radboud University Medical Center
Accession: SCV003934879.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
Sex: female
Geographic origin: Netherlands
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Pathogenic
(Oct 09, 2023)
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no assertion criteria provided
Method: clinical testing
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Polycystic liver disease 3 with or without kidney cysts
Affected status: yes
Allele origin:
germline
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Zotz-Klimas Genetics Lab, MVZ Zotz Klimas
Accession: SCV004041770.1
First in ClinVar: Oct 14, 2023 Last updated: Oct 14, 2023 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Isolated polycystic liver disease genes define effectors of polycystin-1 function. | Besse W | The Journal of clinical investigation | 2017 | PMID: 28375157 |
Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. | Smith ED | Human mutation | 2017 | PMID: 28106320 |
ALG8-CDG: novel patients and review of the literature. | Höck M | Orphanet journal of rare diseases | 2015 | PMID: 26066342 |
Congenital disorders of glycosylation: an update on defects affecting the biosynthesis of dolichol-linked oligosaccharides. | Haeuptle MA | Human mutation | 2009 | PMID: 19862844 |
A new case of ALG8 deficiency (CDG Ih). | Vesela K | Journal of inherited metabolic disease | 2009 | PMID: 19688606 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ALG8 | - | - | - | - |
Text-mined citations for rs376161880 ...
HelpRecord last updated May 08, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.