ClinVar Genomic variation as it relates to human health
NM_013339.4(ALG6):c.257+5G>A
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_013339.4(ALG6):c.257+5G>A
Variation ID: 95529 Accession: VCV000095529.37
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p31.3 1: 63402348 (GRCh38) [ NCBI UCSC ] 1: 63868019 (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 Oct 5, 2015 Feb 20, 2024 Jan 27, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_013339.4:c.257+5G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NC_000001.11:g.63402348G>A NC_000001.10:g.63868019G>A NG_008925.2:g.39759G>A LRG_1260:g.39759G>A LRG_1260t1:c.257+5G>A - Protein change
- Other names
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- Canonical SPDI
- NC_000001.11:63402347: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) 0.00046
The Genome Aggregation Database (gnomAD), exomes 0.00047
The Genome Aggregation Database (gnomAD) 0.00065
Trans-Omics for Precision Medicine (TOPMed) 0.00067
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00077
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
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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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ALG6 | - | - |
GRCh38 GRCh37 |
762 | 795 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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 (6) |
criteria provided, multiple submitters, no conflicts
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Aug 31, 2023 | RCV000081557.22 | |
Pathogenic/Likely pathogenic (13) |
criteria provided, multiple submitters, no conflicts
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Jan 27, 2024 | RCV000192479.28 |
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
(Jul 22, 2015)
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criteria provided, single submitter
Method: clinical testing
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Congenital disorder of glycosylation, type Ic
Affected status: yes
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV000246350.1
First in ClinVar: Oct 05, 2015 Last updated: Oct 05, 2015 |
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Pathogenic
(Mar 30, 2016)
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criteria provided, single submitter
Method: clinical testing
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ALG6-congenital disorder of glycosylation 1C
Affected status: no
Allele origin:
germline
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Knight Diagnostic Laboratories, Oregon Health and Sciences University
Study: CSER-NextGen
Accession: SCV000538013.1 First in ClinVar: Apr 03, 2017 Last updated: Apr 03, 2017 |
Comment:
The c.257+5G>A splicing variant in the ALG6 gene has been previously reported in individuals affected with autosomal recessive congenital disorder of glycosylation Ic, and in … (more)
The c.257+5G>A splicing variant in the ALG6 gene has been previously reported in individuals affected with autosomal recessive congenital disorder of glycosylation Ic, and in trans with a known pathogenic variant (Imbach et al. 2000 and Westphal et al. 2000). This variant is shown to cause the skipping of exon 3, and produces a nonfunctional enzyme as shown by its inability to restore normal glycosylation in a yeast strain lacking a functional ALG6 (Westphal et al. 2000). This c.257+5G>A has been reported in very low frequency in the three control population databases (Exome Sequencing Project [ESP], 1000 Genomes, and ExAc) and has been reported pathogenic in the Emory Genetic Patient Database. Therefore, this collective evidence supports the classification of the c.257+5G>A as a recessive pathogenic variant for congenital disorder of glycosylation type Ic. (less)
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Pathogenic
(Jul 28, 2017)
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criteria provided, single submitter
Method: clinical testing
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ALG6-congenital disorder of glycosylation 1C
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, University Medical Center Utrecht
Study: VKGL Data-share Consensus
Accession: SCV000743997.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
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Pathogenic
(Jun 28, 2013)
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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: SCV000113488.8
First in ClinVar: Jan 17, 2014 Last updated: Dec 19, 2017 |
Number of individuals with the variant: 6
Sex: mixed
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Likely pathogenic
(Oct 01, 2021)
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criteria provided, single submitter
Method: clinical testing
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ALG6-congenital disorder of glycosylation 1C
Affected status: unknown
Allele origin:
unknown
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Myriad Genetics, Inc.
Accession: SCV001194124.3
First in ClinVar: Apr 06, 2020 Last updated: Dec 24, 2022 |
Comment:
NM_013339.3(ALG6):c.257+5G>A is an intronic variant classified as likely pathogenic in the context of congenital disorder of glycosylation type Ic. c.257+5G>A has been observed in cases … (more)
NM_013339.3(ALG6):c.257+5G>A is an intronic variant classified as likely pathogenic in the context of congenital disorder of glycosylation type Ic. c.257+5G>A has been observed in cases with relevant disease (PMID: 27287710, 27959697). Functional assessments of this variant are available in the literature (PMID: 10924277, 10914684). c.257+5G>A has been observed in population frequency databases (gnomAD: NFE 0.09%). In summary, NM_013339.3(ALG6):c.257+5G>A is an intronic variant that has functional support for pathogenicity and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.? (less)
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Pathogenic
(Mar 15, 2022)
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criteria provided, single submitter
Method: clinical testing
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ALG6-congenital disorder of glycosylation 1C
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000611248.2
First in ClinVar: Apr 03, 2017 Last updated: Dec 31, 2022 |
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Pathogenic
(Feb 17, 2023)
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criteria provided, single submitter
Method: clinical testing
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ALG6-congenital disorder of glycosylation 1C
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV003844924.1
First in ClinVar: Mar 26, 2023 Last updated: Mar 26, 2023 |
Comment:
Variant summary: ALG6 c.257+5G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly … (more)
Variant summary: ALG6 c.257+5G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing, including three that predict the variant abolishes a canonical 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing, resulting in a skipping of exon 3 (Imbach_2000). The variant allele was found at a frequency of 0.00047 in 250774 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ALG6 causing Congenital Disorder Of Glycosylation Type 1C (0.00047 vs 0.0011), allowing no conclusion about variant significance. c.257+5G>A has been reported in the literature in multiple compound heterozygous individuals affected with Congenital Disorder Of Glycosylation (Abu Bakkar_2022, Imbach_2000, Morava_2016, Westphal_2000), some of whom were reported to have other (likely) pathogenic variants of ALG6 in trans. These data indicate that the variant is very likely to be associated with disease. One publication reports experimental evidence evaluating the effect of transforming ALG6 missing exon 3 in an alg6-deficient strain of S. cerevisiae, finding that it is unable restore glycosylation activity (Westphal_2000). 12 submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(May 07, 2021)
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criteria provided, single submitter
Method: clinical testing
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ALG6-congenital disorder of glycosylation 1C
Affected status: yes
Allele origin:
maternal
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Accession: SCV003921990.1
First in ClinVar: May 06, 2023 Last updated: May 06, 2023 |
Comment:
0102 - Loss of function is a known mechanism of disease in this gene and is associated with congenital disorder of glycosylation, type Ic (MIM#603147). … (more)
0102 - Loss of function is a known mechanism of disease in this gene and is associated with congenital disorder of glycosylation, type Ic (MIM#603147). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. This variant has been proven to cause in-frame skipping of exon 3 (PMID: 10924277). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2) (103 heterozygotes, 0 homozygotes). (SP) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been previously reported as pathogenic in multiple patients with congenital disorder of glycosylation, type Ic (ClinVar, PMID: 10924277). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Pathogenic
(Aug 31, 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: SCV000568303.8
First in ClinVar: Mar 08, 2017 Last updated: Sep 14, 2023 |
Comment:
Functional studies indicate that c.257+5G>A (reported using alternate nomenclature IVS3+5G>A) transfected cells produce a nonfunctional enzyme that is unable to restore normal glycosylation in a … (more)
Functional studies indicate that c.257+5G>A (reported using alternate nomenclature IVS3+5G>A) transfected cells produce a nonfunctional enzyme that is unable to restore normal glycosylation in a yeast strain lacking functional ALG6 (Westphal et al., 2000); Intronic +5 splice site variant in a gene for which loss of function is a known mechanism of disease, and both splice predictors and evolutionary conservation support a deleterious effect, although in the absence of functional evidence the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 21541726, 23430515, 20447155, 10914684, 27959697, 10924277, 27287710, 31980526, 31589614, 35279850, 36756224) (less)
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Likely pathogenic
(Feb 17, 2021)
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criteria provided, single submitter
Method: clinical testing
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ALG6-congenital disorder of glycosylation 1C
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002021348.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 27, 2024)
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criteria provided, single submitter
Method: clinical testing
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ALG6-congenital disorder of glycosylation 1C
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000824414.7
First in ClinVar: Oct 10, 2018 Last updated: Feb 20, 2024 |
Comment:
This sequence change falls in intron 4 of the ALG6 gene. It does not directly change the encoded amino acid sequence of the ALG6 protein. … (more)
This sequence change falls in intron 4 of the ALG6 gene. It does not directly change the encoded amino acid sequence of the ALG6 protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs199682486, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. This variant has been observed in individuals with congenital disorder of glycosylation 1c (PMID: 10914684, 10924277, 20447155, 23430515). This variant is also known as IVS3+5G>A. ClinVar contains an entry for this variant (Variation ID: 95529). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 3, but is expected to preserve the integrity of the reading-frame (PMID: 10924277). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Sep 16, 2016)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: not provided
Allele origin:
germline
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Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Accession: SCV000511796.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
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Pathogenic
(Sep 21, 2015)
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criteria provided, single submitter
Method: clinical testing
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ALG6-congenital disorder of glycosylation 1C
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Study: VKGL Data-share Consensus
Accession: SCV000745454.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
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Pathogenic
(May 01, 2016)
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no assertion criteria provided
Method: clinical testing
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ALG6-congenital disorder of glycosylation 1C
(Autosomal recessive inheritance)
Affected status: unknown, yes
Allele origin:
paternal,
germline
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Baylor Genetics
Accession: SCV000328845.1
First in ClinVar: Oct 05, 2015 Last updated: Oct 05, 2015 |
Comment:
Our laboratory reported dual molecular diagnoses in ALG6 (NM_013339.3:c.257+5G>A; NM_013339.3:c.988G>T; in trans) and SHOX (NM_000451.3:c.517C>T) in an individual with mild hypotonia, poor feeding, congenital heart … (more)
Our laboratory reported dual molecular diagnoses in ALG6 (NM_013339.3:c.257+5G>A; NM_013339.3:c.988G>T; in trans) and SHOX (NM_000451.3:c.517C>T) in an individual with mild hypotonia, poor feeding, congenital heart disease (VSD, PFO, PDA), seizure disorder, dysmorphic facies, small chest wall, bowed lower legs, apparently short upper extremities, shallow sacral dimple, small for gestational age and a history of prematurity and intrauterine growth restriction. (less)
Observation 1: Observation 2: |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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ALG6-congenital disorder of glycosylation 1C
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: SCV000734047.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
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Pathogenic
(Sep 16, 2020)
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no assertion criteria provided
Method: clinical testing
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Congenital disorder of glycosylation type 1c
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV001456276.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 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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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: SCV001951808.1 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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Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV001808132.1 First in ClinVar: Aug 25, 2021 Last updated: Aug 25, 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: SCV002036640.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021 |
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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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Synergistic use of glycomics and single-molecule molecular inversion probes for identification of congenital disorders of glycosylation type-1. | Abu Bakar N | Journal of inherited metabolic disease | 2022 | PMID: 35279850 |
Resolution of Disease Phenotypes Resulting from Multilocus Genomic Variation. | Posey JE | The New England journal of medicine | 2017 | PMID: 27959697 |
ALG6-CDG: a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioral and limb anomalies. | Morava E | Journal of inherited metabolic disease | 2016 | PMID: 27287710 |
ALG6-CDG in South Africa: Genotype-Phenotype Description of Five Novel Patients. | Dercksen M | JIMD reports | 2013 | PMID: 23430515 |
Skeletal dysplasia with brachytelephalangy in a patient with a congenital disorder of glycosylation due to ALG6 gene mutations. | Drijvers JM | Clinical genetics | 2010 | PMID: 20447155 |
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. | Buratti E | Nucleic acids research | 2007 | PMID: 17576681 |
Analysis of multiple mutations in the hALG6 gene in a patient with congenital disorder of glycosylation Ic. | Westphal V | Molecular genetics and metabolism | 2000 | PMID: 10924277 |
Multi-allelic origin of congenital disorder of glycosylation (CDG)-Ic. | Imbach T | Human genetics | 2000 | PMID: 10914684 |
Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ALG6 | - | - | - | - |
Text-mined citations for rs199682486 ...
HelpRecord last updated Mar 17, 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.