VCV000962673.21 - ClinVar

NM_000018.4(ACADVL):c.62+1G>A

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.

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_000018.4(ACADVL):c.62+1G>A

Variation ID: 962673 Accession: VCV000962673.21

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 17p13.1 17: 7220047 (GRCh38) [ NCBI UCSC ] 17: 7123366 (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	Jul 16, 2020	Jun 17, 2024	Jan 2, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000018.4:c.62+1G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice donor
NM_001033859.3:c.62+1G>A		splice donor
NM_001270447.2:c.132-75G>A		intron variant
NM_001270448.2:c.-241G>A		5 prime UTR
NM_001321074.1:c.-1198C>T		5 prime UTR
NM_001365.4:c.-1198C>T
NR_135527.1:n.4C>T		non-coding transcript variant
NC_000017.11:g.7220047G>A
NC_000017.10:g.7123366G>A
NG_007975.1:g.5214G>A
NG_008391.2:g.5004C>T
NG_008391.3:g.5003C>T
NG_194534.1:g.86G>A

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000017.11:7220046:G:A

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.

Links

dbSNP: rs2071111529 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.
DLG4		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	163	336
ACADVL		-	-	GRCh38 GRCh37	1725	1937

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.
Very long chain acyl-CoA dehydrogenase deficiency	Pathogenic/Likely pathogenic (4)	criteria provided, multiple submitters, no conflicts	Jan 2, 2024	RCV001236568.19

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 (Apr 09, 2022)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Very long chain acyl-CoA dehydrogenase deficiency Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV002511768.1 First in ClinVar: May 16, 2022 Last updated: May 16, 2022	Publications: PubMed (2) PubMed: 9973285‚ 23169530 Comment: Variant summary: ACADVL c.62+1G>A alters a conserved nucleotide located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered … (more) Variant summary: ACADVL c.62+1G>A alters a conserved nucleotide located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes the canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 227052 control chromosomes. c.62+1G>A has been reported in the literature in at-least one individual affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency (example, Andresen_1999). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
Likely pathogenic (Jun 25, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Very long chain acyl-CoA dehydrogenase deficiency Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001409296.5 First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024	Publications: PubMed (3) PubMed: 9973285‚ 16199547‚ 11590124 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: 962673). Disruption of this splice site has been observed in individual(s) with very long chain acyl-CoA dehydrogenase deficiency (PMID: 9973285). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 1 of the ACADVL 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 ACADVL are known to be pathogenic (PMID: 9973285, 11590124). (less)
Pathogenic (Jan 02, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Very long chain acyl-CoA dehydrogenase deficiency Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV005058215.1 First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024
Likely pathogenic (Feb 04, 2020)	no assertion criteria provided Method: clinical testing	Very long chain acyl-CoA dehydrogenase deficiency Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV002088734.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022

Comment:

Variant summary: ACADVL c.62+1G>A alters a conserved nucleotide located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes the canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 227052 control chromosomes. c.62+1G>A has been reported in the literature in at-least one individual affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency (example, Andresen_1999). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

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: 962673). Disruption of this splice site has been observed in individual(s) with very long chain acyl-CoA dehydrogenase deficiency (PMID: 9973285). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 1 of the ACADVL 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 ACADVL are known to be pathogenic (PMID: 9973285, 11590124).

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
Novel mutations in the gene encoding very long-chain acyl-CoA dehydrogenase identified in patients with partial carnitine palmitoyltransferase II deficiency.	Isackson PJ	Muscle & nerve	2013	PMID: 23169530
Splicing in action: assessing disease causing sequence changes.	Baralle D	Journal of medical genetics	2005	PMID: 16199547
Gestational, pathologic and biochemical differences between very long-chain acyl-CoA dehydrogenase deficiency and long-chain acyl-CoA dehydrogenase deficiency in the mouse.	Cox KB	Human molecular genetics	2001	PMID: 11590124
Clear correlation of genotype with disease phenotype in very-long-chain acyl-CoA dehydrogenase deficiency.	Andresen BS	American journal of human genetics	1999	PMID: 9973285

Text-mined citations for rs2071111529 ...

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 25, 2024

ClinVar Genomic variation as it relates to human health

NM_000018.4(ACADVL):c.62+1G>A

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs2071111529 ...