Published functional studies found this variant is associated with reduced UDP-galactose transport (Ng BG et al., 2013); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27743886, 32820034, 23561849, 25778940, 28771251, 29907092, 30746764)
ClinVar Genomic variation as it relates to human health
NM_005660.3(SLC35A2):c.991G>A (p.Val331Ile)
Germline
Classification
Help
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.
(5)
Help
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.
Pathogenic
5
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_005660.3(SLC35A2):c.991G>A (p.Val331Ile)
Variation ID: 50364 Accession: VCV000050364.11
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: Xp11.23 X: 48904918 (GRCh38) [ NCBI UCSC ] X: 48762195 (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 Sep 29, 2015 Mar 10, 2024 Mar 29, 2022 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_005660.3:c.991G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_005651.1:p.Val331Ile missense NM_001032289.3:c.427-26G>A intron variant NM_001042498.3:c.991G>A NP_001035963.1:p.Val331Ile missense NM_001282647.2:c.427-26G>A intron variant NM_001282648.2:c.355-26G>A intron variant NM_001282649.2:c.808G>A NP_001269578.1:p.Val270Ile missense NM_001282650.2:c.1030G>A NP_001269579.1:p.Val344Ile missense NM_001282651.2:c.1075G>A NP_001269580.1:p.Val359Ile missense NC_000023.11:g.48904918C>T NC_000023.10:g.48762195C>T NG_015967.1:g.12001C>T NG_015967.2:g.11990C>T NG_034300.1:g.12041G>A P78381:p.Val331Ile - Protein change
- V331I, V344I, V359I, V270I
- Other names
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- Canonical SPDI
- NC_000023.11:48904917:C:T
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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.
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- Links
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 | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
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. |
|||
| SLC35A2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh38 GRCh37 |
- | - | |
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. |
|---|---|---|---|---|
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Feb 10, 2022 | RCV000043515.17 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Mar 29, 2022 | RCV000498343.3 |
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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|---|---|---|---|---|---|
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Pathogenic
(Mar 29, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000589670.4
First in ClinVar: Aug 20, 2017 Last updated: Mar 04, 2023 |
Comment:
Published functional studies found this variant is associated with reduced UDP-galactose transport (Ng BG et al., 2013); Not observed at significant frequency in large population … (more)
Published functional studies found this variant is associated with reduced UDP-galactose transport (Ng BG et al., 2013); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27743886, 32820034, 23561849, 25778940, 28771251, 29907092, 30746764) (less)
|
|
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Pathogenic
(Aug 18, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
CONGENITAL DISORDER OF GLYCOSYLATION, TYPE IIm
Affected status: yes
Allele origin:
germline
|
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
Accession: SCV001984813.1
First in ClinVar: Oct 30, 2021 Last updated: Oct 30, 2021 |
Comment:
This variant has been previously reported as a de novo change in multiple, unrelated, patients with congenital disorder of glycosylation (PMID: 23561849, 28771251, 29907092, 30746764). … (more)
This variant has been previously reported as a de novo change in multiple, unrelated, patients with congenital disorder of glycosylation (PMID: 23561849, 28771251, 29907092, 30746764). It is absent from the gnomAD population database and thus is presumed to be rare. The c.991G>A (p.Val331Ile) variant affects a highly conserved amino acid; however, in silico tools used to predict the effect of this variant on protein function yield discordant results. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.991G>A (p.Val331Ile) variant is classified as Pathogenic. (less)
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Pathogenic
(Feb 10, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
SLC35A2-congenital disorder of glycosylation
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001210595.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with early infantile epileptic encephalopathy and/or … (more)
This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with early infantile epileptic encephalopathy and/or SLC35A2-CDG (PMID: 23561849, 28771251, 29907092, 30746764; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 50364). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic. This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 331 of the SLC35A2 protein (p.Val331Ile). (less)
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Pathogenic
(Apr 04, 2013)
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no assertion criteria provided
Method: literature only
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CONGENITAL DISORDER OF GLYCOSYLATION, TYPE IIm, SOMATIC MOSAIC
Affected status: not provided
Allele origin:
somatic
|
OMIM
Accession: SCV000067385.5
First in ClinVar: May 18, 2013 Last updated: Mar 10, 2024 |
Comment on evidence:
In a 6-year-old boy (CDG-352) with congenital disorder of glycosylation type IIm (CDG2M; 300896), Ng et al. (2013) identified a de novo hemizygous c.991G-A transition … (more)
In a 6-year-old boy (CDG-352) with congenital disorder of glycosylation type IIm (CDG2M; 300896), Ng et al. (2013) identified a de novo hemizygous c.991G-A transition (c.991G-A, NM_001042493.2) in the SLC35A2 gene, resulting in a val331-to-ile (V331I) substitution and predicted to cause improper positioning in the membrane. The mutation was present in the somatic mosaic state in the patient and was not found in several large control databases. (less)
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Pathogenic
(Nov 14, 2013)
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no assertion criteria provided
Method: research
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CONGENITAL DISORDER OF GLYCOSYLATION, TYPE IIm
Affected status: yes
Allele origin:
de novo
|
University of Washington Center for Mendelian Genomics, University of Washington
Accession: SCV000246122.1
First in ClinVar: Sep 29, 2015 Last updated: Sep 29, 2015 |
Number of individuals with the variant: 1
Sex: male
|
Comment:
Comment:
This variant has been previously reported as a de novo change in multiple, unrelated, patients with congenital disorder of glycosylation (PMID: 23561849, 28771251, 29907092, 30746764). It is absent from the gnomAD population database and thus is presumed to be rare. The c.991G>A (p.Val331Ile) variant affects a highly conserved amino acid; however, in silico tools used to predict the effect of this variant on protein function yield discordant results. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.991G>A (p.Val331Ile) variant is classified as Pathogenic.
Comment:
This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with early infantile epileptic encephalopathy and/or SLC35A2-CDG (PMID: 23561849, 28771251, 29907092, 30746764; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 50364). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic. This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 331 of the SLC35A2 protein (p.Val331Ile).
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. |
Comment:
Published functional studies found this variant is associated with reduced UDP-galactose transport (Ng BG et al., 2013); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27743886, 32820034, 23561849, 25778940, 28771251, 29907092, 30746764)
Comment:
This variant has been previously reported as a de novo change in multiple, unrelated, patients with congenital disorder of glycosylation (PMID: 23561849, 28771251, 29907092, 30746764). It is absent from the gnomAD population database and thus is presumed to be rare. The c.991G>A (p.Val331Ile) variant affects a highly conserved amino acid; however, in silico tools used to predict the effect of this variant on protein function yield discordant results. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.991G>A (p.Val331Ile) variant is classified as Pathogenic.
Comment:
This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with early infantile epileptic encephalopathy and/or SLC35A2-CDG (PMID: 23561849, 28771251, 29907092, 30746764; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 50364). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic. This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 331 of the SLC35A2 protein (p.Val331Ile).
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Clinical, neuroradiological, and biochemical features of SLC35A2-CDG patients. | Vals MA | Journal of inherited metabolic disease | 2019 | PMID: 30746764 |
| Mosaicism of the UDP-Galactose transporter SLC35A2 in a female causing a congenital disorder of glycosylation: a case report. | Westenfield K | BMC medical genetics | 2018 | PMID: 29907092 |
| Improved diagnostic yield compared with targeted gene sequencing panels suggests a role for whole-genome sequencing as a first-tier genetic test. | Lionel AC | Genetics in medicine : official journal of the American College of Medical Genetics | 2018 | PMID: 28771251 |
| Mosaicism of the UDP-galactose transporter SLC35A2 causes a congenital disorder of glycosylation. | Ng BG | American journal of human genetics | 2013 | PMID: 23561849 |
Text-mined citations for rs587776961 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Nov 10, 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.