VCV000239583.13 - ClinVar

NM_003896.4(ST3GAL5):c.82+1G>C

Germline

Classification

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.

(4)

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.

Conflicting classifications of pathogenicity
Likely pathogenic(2); Uncertain significance(2)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_003896.4(ST3GAL5):c.82+1G>C

Variation ID: 239583 Accession: VCV000239583.13

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2p11.2 2: 85888823 (GRCh38) [ NCBI UCSC ] 2: 86115946 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	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 10, 2018	May 1, 2024	Nov 1, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_003896.4:c.82+1G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice donor
NM_001354223.2:c.-881+1G>C		splice donor
NM_001354224.2:c.-543+1G>C		splice donor
NM_001354226.2:c.-480+1G>C		splice donor
NM_001354227.2:c.-190+1G>C		splice donor
NM_001354229.2:c.-134+1G>C		splice donor
NM_001354233.2:c.-920+1G>C		splice donor
NM_001363847.1:c.82+1G>C		splice donor
NC_000002.12:g.85888823C>G
NC_000002.11:g.86115946C>G
NG_012807.1:g.5212G>C
NG_012807.2:g.5211G>C
NG_167257.1:g.152C>G

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000002.12:85888822:C:G

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD) 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00001

Links

ClinGen: CA10582108 dbSNP: rs878854615 VarSome

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
Gene	OMIM	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.
LOC129934236	-	-	-	GRCh38	-	74
ST3GAL5		-	-	GRCh38 GRCh37	381	477

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.
GM3 synthase deficiency	Conflicting interpretations of pathogenicity (3)	criteria provided, conflicting classifications	Sep 10, 2023	RCV000229539.15
Inborn genetic diseases	Uncertain significance (1)	criteria provided, single submitter	Nov 1, 2023	RCV004020809.1

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.
Likely pathogenic (Sep 10, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	GM3 synthase deficiency Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000288016.7 First in ClinVar: Jul 01, 2016 Last updated: Feb 20, 2024	Publications: PubMed (5) PubMed: 28492532‚ 16199547‚ 15502825‚ 22990144‚ 27232954 Comment: In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has … (more) In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 239583). This variant has not been reported in the literature in individuals affected with ST3GAL5-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 1 of the ST3GAL5 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ST3GAL5 are known to be pathogenic (PMID: 15502825, 22990144, 27232954). (less)
Uncertain significance (Mar 16, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019) Method: clinical testing	GM3 synthase deficiency Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000914945.1 First in ClinVar: May 27, 2019 Last updated: May 27, 2019	Comment: The ST3GAL5 c.82+1G>C variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. A literature … (more) The ST3GAL5 c.82+1G>C variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. A literature search was performed for the gene and cDNA change. No publications were found based on this search. Based on the variant frequency, disease prevalence, disease penetrance, and inheritance mode, this variant could not be ruled out of causing disease. Due to the potential impact of splice donor variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance, but suspicious for pathogenicity for Amish infantile epilepsy syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
Likely pathogenic (Nov 15, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	GM3 synthase deficiency Affected status: yes Allele origin: unknown	Baylor Genetics Accession: SCV001520496.1 First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021	Comment: This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Uncertain significance (Nov 01, 2023)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV004958474.1 First in ClinVar: May 01, 2024 Last updated: May 01, 2024	Publications: PubMed (1) PubMed: 31440721 Comment: The c.82+1G>C intronic variant results from a G to C substitution one nucleotide after coding exon 1 of the ST3GAL5 gene. This region of the … (more) The c.82+1G>C intronic variant results from a G to C substitution one nucleotide after coding exon 1 of the ST3GAL5 gene. This region of the ST3GAL5 gene is excluded from other biologically relevant ST3GAL5 transcripts. This allele was reported in one heterozygous individual in population-based cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. (less)

Comment:

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 239583). This variant has not been reported in the literature in individuals affected with ST3GAL5-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 1 of the ST3GAL5 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ST3GAL5 are known to be pathogenic (PMID: 15502825, 22990144, 27232954).

Comment:

The ST3GAL5 c.82+1G>C variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. A literature search was performed for the gene and cDNA change. No publications were found based on this search. Based on the variant frequency, disease prevalence, disease penetrance, and inheritance mode, this variant could not be ruled out of causing disease. Due to the potential impact of splice donor variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance, but suspicious for pathogenicity for Amish infantile epilepsy syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

Comment:

The c.82+1G>C intronic variant results from a G to C substitution one nucleotide after coding exon 1 of the ST3GAL5 gene. This region of the ST3GAL5 gene is excluded from other biologically relevant ST3GAL5 transcripts. This allele was reported in one heterozygous individual in population-based cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Possible precision medicine implications from genetic testing using combined detection of sequence and intragenic copy number variants in a large cohort with childhood epilepsy.	Truty R	Epilepsia open	2019	PMID: 31440721
GM3 synthase deficiency due to ST3GAL5 variants in two Korean female siblings: Masquerading as Rett syndrome-like phenotype.	Lee JS	American journal of medical genetics. Part A	2016	PMID: 27232954
Refractory epilepsy and mitochondrial dysfunction due to GM3 synthase deficiency.	Fragaki K	European journal of human genetics : EJHG	2013	PMID: 22990144
Splicing in action: assessing disease causing sequence changes.	Baralle D	Journal of medical genetics	2005	PMID: 16199547
Infantile-onset symptomatic epilepsy syndrome caused by a homozygous loss-of-function mutation of GM3 synthase.	Simpson MA	Nature genetics	2004	PMID: 15502825

Text-mined citations for rs878854615 ...

These 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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_003896.4(ST3GAL5):c.82+1G>C

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs878854615 ...