VCV000984711.30 - ClinVar

NM_001080.3(ALDH5A1):c.1402+1G>T

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.

(8)

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/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001080.3(ALDH5A1):c.1402+1G>T

Variation ID: 984711 Accession: VCV000984711.30

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 6p22.3 6: 24532178 (GRCh38) [ NCBI UCSC ] 6: 24532406 (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	Nov 14, 2020	Nov 10, 2024	Apr 26, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001080.3:c.1402+1G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice donor
NM_001368954.1:c.1258+1G>T		splice donor
NM_170740.1:c.1441+1G>T		splice donor
NC_000006.12:g.24532178G>T
NC_000006.11:g.24532406G>T
NG_008161.1:g.42210G>T

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000006.12:24532177:G:T

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

effect on RNA splicing function; Variation Ontology [ VariO:0397]

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.

Links

dbSNP: rs762290992 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.
ALDH5A1		-	-	GRCh38 GRCh37	617	835

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.
Succinate-semialdehyde dehydrogenase deficiency	Pathogenic/Likely pathogenic (5)	criteria provided, multiple submitters, no conflicts	Jul 17, 2023	RCV001264821.10
not provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Apr 26, 2024	RCV001726474.21
See cases	Pathogenic (1)	criteria provided, single submitter	Sep 7, 2022	RCV002287488.2

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 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 (Mar 01, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Succinate-semialdehyde dehydrogenase deficiency (Autosomal recessive inheritance) Affected status: yes Allele origin: biparental	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV001443013.1 First in ClinVar: Nov 14, 2020 Last updated: Nov 14, 2020	Comment: Review of the variants reported in Reuter et al., 2017, PMID: 28097321: PVS1_Strong,PM2,PM3 Clinical Features: mild ID (present) , short stature (present) , muscular hypotonia (present)
Pathogenic (Sep 07, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	see cases Affected status: yes Allele origin: unknown	Institute of Human Genetics, University Hospital Muenster Accession: SCV002578020.1 First in ClinVar: Oct 08, 2022 Last updated: Oct 08, 2022	Comment: ACMG categories: PVS1,PM2,PP3,PP5 Number of individuals with the variant: 1 Clinical Features: Infantile muscular hypotonia (present) , Abnormal periventricular white matter morphology (present) , Periventricular leukomalacia (present) , Leukodystrophy (present) , Poor head control (present) , Delayed … (more) Infantile muscular hypotonia (present) , Abnormal periventricular white matter morphology (present) , Periventricular leukomalacia (present) , Leukodystrophy (present) , Poor head control (present) , Delayed speech and language development (present) , Involuntary movements (present) , Global developmental delay (present) , Mitochondrial inheritance (present) (less) Age: 0-9 years Sex: male Tissue: blood
Pathogenic (Mar 08, 2021)	criteria provided, single submitter (Martin et al. (J Child Neurol. 2021)) Method: curation	Succinate-semialdehyde dehydrogenase deficiency Affected status: yes Allele origin: germline	Elsea Laboratory, Baylor College of Medicine Accession: SCV002820037.1 First in ClinVar: Jan 15, 2023 Last updated: Jan 15, 2023 Comment: sequence_variant_affecting_splicing; IVS9+1G>T	Publications: PubMed (1) PubMed: 9683595
Pathogenic (Jun 18, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Succinate-semialdehyde dehydrogenase deficiency Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV004293255.1 First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024	Publications: PubMed (3) PubMed: 17576681‚ 9536098‚ 9683595 Comment: For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing … (more) For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that disruption of this splice site results in skipping of exon 9 and introduces a new termination codon (PMID: 9683595). However the mRNA is not expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 984711). Disruption of this splice site has been observed in individual(s) with succinic semialdehyde dehydrogenase deficiency (PMID: 9683595). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 9 of the ALDH5A1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely disrupts the C-terminus of the protein. (less)
Pathogenic (Jul 17, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Succinate-semialdehyde dehydrogenase deficiency (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV005086785.1 First in ClinVar: Jul 23, 2024 Last updated: Jul 23, 2024	Publications: PubMed (4) PubMed: 9683595‚ 23430864‚ 31267348‚ 34540776 Comment: Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more) Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with succinic semialdehyde dehydrogenase deficiency (MIM#271980). (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 functionally proven to result in exon 9 skipping, with the formation of a premature termination codon. The resulting protein (p.(Phe449Leufs*54)) is expected to escape nonsense-mediated decay, but result in a truncated protein (PMID: 9683595). (SP) 0252 - This variant is homozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0311 - An alternative nucleotide change at the same canonical splice site, is present in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0600 - Variant results in the partial loss of the annotated aldehyde dehydrogenase family domain (DECIPHER). (I) 0701 - Protein truncating variants or canonical splice variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. These variants have been reported multiple times as pathogenic, and observed in compound heterozygous or homozygous individuals with succinic semialdehyde dehydrogenase deficiency (SSADH; ClinVar, PMID: 31267348, PMID: 23430864). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported several times as likely pathogenic or pathogenic, and observed in homozygous individuals with SSADH deficiency or cerebral palsy (PMID: 9683595, PMID: 34540776). (SP) 1209 - This variant has been shown to be both maternally and paternally inherited (biallelic, by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
Pathogenic (Aug 01, 2021)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001961936.20 First in ClinVar: Oct 08, 2021 Last updated: Oct 20, 2024	Number of individuals with the variant: 3
Pathogenic (Apr 26, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV005389316.1 First in ClinVar: Nov 10, 2024 Last updated: Nov 10, 2024	Comment: Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; … (more) Canonical splice site variant predicted to result in a null allele 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: 28191889, 36964972, 9683595, 34426522, 25525159) (less)
Pathogenic (Jun 10, 2021)	no assertion criteria provided Method: clinical testing	Succinate-semialdehyde dehydrogenase deficiency Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, University Hospital Schleswig-Holstein Accession: SCV002011761.1 First in ClinVar: Nov 06, 2021 Last updated: Nov 06, 2021

Comment:

For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that disruption of this splice site results in skipping of exon 9 and introduces a new termination codon (PMID: 9683595). However the mRNA is not expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 984711). Disruption of this splice site has been observed in individual(s) with succinic semialdehyde dehydrogenase deficiency (PMID: 9683595). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 9 of the ALDH5A1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely disrupts the C-terminus of the protein.

Comment:

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with succinic semialdehyde dehydrogenase deficiency (MIM#271980). (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 functionally proven to result in exon 9 skipping, with the formation of a premature termination codon. The resulting protein (p.(Phe449Leufs*54)) is expected to escape nonsense-mediated decay, but result in a truncated protein (PMID: 9683595). (SP) 0252 - This variant is homozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0311 - An alternative nucleotide change at the same canonical splice site, is present in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0600 - Variant results in the partial loss of the annotated aldehyde dehydrogenase family domain (DECIPHER). (I) 0701 - Protein truncating variants or canonical splice variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. These variants have been reported multiple times as pathogenic, and observed in compound heterozygous or homozygous individuals with succinic semialdehyde dehydrogenase deficiency (SSADH; ClinVar, PMID: 31267348, PMID: 23430864). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported several times as likely pathogenic or pathogenic, and observed in homozygous individuals with SSADH deficiency or cerebral palsy (PMID: 9683595, PMID: 34540776). (SP) 1209 - This variant has been shown to be both maternally and paternally inherited (biallelic, by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Comment:

Canonical splice site variant predicted to result in a null allele 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: 28191889, 36964972, 9683595, 34426522, 25525159)

Germline Functional Evidence

Functional Help The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence	Method Help A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter.	Result Help A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
effect on RNA splicing function (VariO:0397)			Elsea Laboratory, Baylor College of Medicine Accession: SCV002820037.1	Publications PubMed (1)

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Genetic Testing in Various Neurodevelopmental Disorders Which Manifest as Cerebral Palsy: A Case Study From Iran.	Nejabat M	Frontiers in pediatrics	2021	PMID: 34540776
Novel mutations in two unrelated Italian patients with SSADH deficiency.	Balzarini M	Metabolic brain disease	2019	PMID: 31267348
Efficacy of vigabatrin intervention in a mild phenotypic expression of succinic semialdehyde dehydrogenase deficiency.	Casarano M	JIMD reports	2012	PMID: 23430864
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
Two exon-skipping mutations as the molecular basis of succinic semialdehyde dehydrogenase deficiency (4-hydroxybutyric aciduria).	Chambliss KL	American journal of human genetics	1998	PMID: 9683595
Statistical features of human exons and their flanking regions.	Zhang MQ	Human molecular genetics	1998	PMID: 9536098

Text-mined citations for rs762290992 ...

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 Nov 10, 2024

ClinVar Genomic variation as it relates to human health

NM_001080.3(ALDH5A1):c.1402+1G>T

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs762290992 ...