ClinVar Genomic variation as it relates to human health
NM_003896.4(ST3GAL5):c.1063G>A (p.Glu355Lys)
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.
Pathogenic(2); Likely pathogenic(1); Uncertain significance(2)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_003896.4(ST3GAL5):c.1063G>A (p.Glu355Lys)
Variation ID: 140575 Accession: VCV000140575.12
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2p11.2 2: 85840338 (GRCh38) [ NCBI UCSC ] 2: 86067461 (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 18, 2016 Sep 16, 2024 Jun 18, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_003896.4:c.1063G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003887.3:p.Glu355Lys missense NM_001042437.2:c.994G>A NP_001035902.1:p.Glu332Lys missense NM_001354223.2:c.679G>A NP_001341152.1:p.Glu227Lys missense NM_001354224.2:c.679G>A NP_001341153.1:p.Glu227Lys missense NM_001354226.2:c.679G>A NP_001341155.1:p.Glu227Lys missense NM_001354227.2:c.979G>A NP_001341156.1:p.Glu327Lys missense NM_001354229.2:c.979G>A NP_001341158.1:p.Glu327Lys missense NM_001354233.2:c.679G>A NP_001341162.1:p.Glu227Lys missense NM_001354234.1:c.679G>A NP_001341163.1:p.Glu227Lys missense NM_001354238.1:c.979G>A NP_001341167.1:p.Glu327Lys missense NM_001354247.1:c.340G>A NP_001341176.1:p.Glu114Lys missense NM_001354248.1:c.679G>A NP_001341177.1:p.Glu227Lys missense NM_001363847.1:c.904G>A NP_001350776.1:p.Glu302Lys missense NC_000002.12:g.85840338C>T NC_000002.11:g.86067461C>T NG_012807.1:g.53697G>A - Protein change
- E332K, E355K, E327K, E227K, E114K, E302K
- Other names
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- Canonical SPDI
- NC_000002.12:85840337: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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0.00040 (T)
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Allele frequency
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The frequency of the allele represented by this VCV record.
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The Genome Aggregation Database (gnomAD), exomes 0.00002
Exome Aggregation Consortium (ExAC) 0.00003
Trans-Omics for Precision Medicine (TOPMed) 0.00008
The Genome Aggregation Database (gnomAD) 0.00013
1000 Genomes Project 0.00040
1000 Genomes Project 30x 0.00047
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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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| ST3GAL5 | - | - |
GRCh38 GRCh37 |
381 | 477 | |
Conditions - Germline
| Condition
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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
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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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| Conflicting interpretations of pathogenicity (5) |
criteria provided, conflicting classifications
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Jun 18, 2024 | RCV000128792.12 | |
| Likely pathogenic (1) |
criteria provided, single submitter
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Sep 16, 2023 | RCV003151747.2 |
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
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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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Uncertain significance
(Feb 27, 2020)
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criteria provided, single submitter
Method: clinical testing
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GM3 synthase deficiency
Affected status: yes
Allele origin:
unknown
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Baylor Genetics
Accession: SCV001520491.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
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Pathogenic
(Jun 18, 2024)
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criteria provided, single submitter
Method: clinical testing
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GM3 synthase deficiency
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV005204699.1
First in ClinVar: Sep 16, 2024 Last updated: Sep 16, 2024 |
Comment:
Variant summary: ST3GAL5 c.1063G>A (p.Glu355Lys), also reported as E332K, results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico … (more)
Variant summary: ST3GAL5 c.1063G>A (p.Glu355Lys), also reported as E332K, results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251394 control chromosomes. c.1063G>A has been reported in the literature in the homozygous or presumed compound heterozygous states in multiple individuals affected with GM3 synthase deficiency (example, Boccuto_2014, Heide_2022). These data indicate that the variant is likely to be associated with disease. This variant was shown to lack detectable enzymatic activity in vitro and in patient cells (example, Indellicato_2019, Boccuto_2014). The following publications have been ascertained in the context of this evaluation (PMID: 24026681, 34906476, 30576498). ClinVar contains an entry for this variant (Variation ID: 140575). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Jan 08, 2018)
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criteria provided, single submitter
Method: clinical testing
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GM3 synthase deficiency
Affected status: unknown
Allele origin:
unknown
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Illumina Laboratory Services, Illumina
Accession: SCV004801587.1
First in ClinVar: Mar 23, 2024 Last updated: Mar 23, 2024 |
Comment:
The ST3GAL5 c.1063G>A p.(Glu355Lys) missense variant has been reported in the literature in three siblings of African American ancestry affected with salt and pepper developmental … (more)
The ST3GAL5 c.1063G>A p.(Glu355Lys) missense variant has been reported in the literature in three siblings of African American ancestry affected with salt and pepper developmental regression syndrome (Boccuto et al. 2014). The p.Glu355Lys variant was absent in 561 normal individuals from the same geographic area (South Carolina), of which 216 were African Americans. The c.1063G>A variant is not observed in version 2.1.1 of the Genome Aggregation Database. Functional studies conducted in patient cells, animal models, in vitro and structural modelling demonstrated that this variant impacts protein function (Boccuto et al. 2014). Based on the collective evidence the c.1063G>A p.(Glu355Lys) variant is classified as pathogenic for salt and pepper developmental regression syndrome. (less)
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Uncertain significance
(Sep 01, 2022)
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criteria provided, single submitter
Method: clinical testing
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GM3 synthase deficiency
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001223953.4
First in ClinVar: Apr 15, 2020 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 355 of the ST3GAL5 protein … (more)
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 355 of the ST3GAL5 protein (p.Glu355Lys). This variant is present in population databases (rs534438354, gnomAD 0.04%). This missense change has been observed in individual(s) with clinical features of ST3GAL5-related conditions (PMID: 24026681). This variant is also known as c.994G>A, p.E332K. ClinVar contains an entry for this variant (Variation ID: 140575). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects ST3GAL5 function (PMID: 30576498). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Likely pathogenic
(Sep 16, 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: SCV003840583.2
First in ClinVar: Mar 18, 2023 Last updated: Sep 22, 2023 |
Comment:
Published functional studies demonstrate that the variant results in loss of enzyme function (Indellicato et al., 2019); In silico analysis supports that this missense variant … (more)
Published functional studies demonstrate that the variant results in loss of enzyme function (Indellicato et al., 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24026681, 35628171, 34906476, 30576498, 36833282) (less)
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Pathogenic
(Jan 15, 2014)
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no assertion criteria provided
Method: literature only
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SALT AND PEPPER DEVELOPMENTAL REGRESSION SYNDROME
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000172440.2
First in ClinVar: Jul 27, 2014 Last updated: Sep 18, 2016 |
Comment on evidence:
In 2 sibs originally reported by Saul et al. (1983) as having 'salt and pepper' mental retardation syndrome (SPDRS; 609056), Boccuto et al. (2014) identified … (more)
In 2 sibs originally reported by Saul et al. (1983) as having 'salt and pepper' mental retardation syndrome (SPDRS; 609056), Boccuto et al. (2014) identified a homozygous c.994G-A transition in exon 7 of the ST3GAL5 gene, resulting in a glu332-to-lys (E332K) substitution in the S-motif of the protein. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the dbSNP (build 137) database or in 561 individuals from South Carolina, the geographic region of the family. Molecular modeling studies suggested that the E332K substitution would destabilize the protein. Patient fibroblasts showed no GM2 or GM3, consistent with a loss of ST3GAL5 function. Analysis of the glycolipid profile in patient cells and plasma showed a shift toward ceramides with longer fatty acid chain length. Microarray analysis of glycosyltransferase mRNAs detected modestly increased expression of ST3GAL5 as well as greater changes in transcripts encoding enzymes that lie downstream of ST3GAL5 and in other glycosphingolipid biosynthetic pathways. Comprehensive glycomic analysis of N-linked, O-linked, and glycosphingolipid glycans revealed collateral modulation of glycoprotein sialylation in response to the loss of complex gangliosides. Morpholino knockdown of st3gal5 in zebrafish embryos caused increased neuronal cell death that could be rescued by expression of the wildtype gene. The findings indicated that human neural cells are extremely sensitive to ST3GAL5 deficiency and altered glycosphingolipid synthesis. (less)
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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
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| GM3 synthase deficiency in non-Amish patients. | Heide S | Genetics in medicine : official journal of the American College of Medical Genetics | 2022 | PMID: 34906476 |
| Total loss of GM3 synthase activity by a normally processed enzyme in a novel variant and in all ST3GAL5 variants reported to cause a distinct congenital disorder of glycosylation. | Indellicato R | Glycobiology | 2019 | PMID: 30576498 |
| A mutation in a ganglioside biosynthetic enzyme, ST3GAL5, results in salt & pepper syndrome, a neurocutaneous disorder with altered glycolipid and glycoprotein glycosylation. | Boccuto L | Human molecular genetics | 2014 | PMID: 24026681 |
| Saul, R. A., Wilkes, G., Stevenson, R. E. 'Salt-and-pepper' pigmentary changes with severe mental retardation: a new neurocutaneous syndrome? Proc. Greenwood Genet. Center 2: 6-9, 1983. | - | - | - | - |
Text-mined citations for rs534438354 ...
HelpRecord last updated Sep 29, 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.