VCV000021022.34 - ClinVar

NM_000018.4(ACADVL):c.49C>T (p.Leu17Phe)

Germline

Top reviewed classifications are shown here.

Submission summary:

13 submissions

13 submitters

3 conditions

Reviewed by expert panel

Benign

Sep 2022 by ClinGen ACADVL… FDA Recognized Database

for Very long chain acyl-CoA dehydrogenase deficiency

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000018.4(ACADVL):c.49C>T (p.Leu17Phe)

Variation ID: 21022 Accession: VCV000021022.34

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 17p13.1 17: 7220033 (GRCh38) [ NCBI UCSC ] 17: 7123352 (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	Apr 4, 2013	Sep 29, 2024	Sep 22, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_000018.4:c.49C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000009.1:p.Leu17Phe	missense
NM_001033859.3:c.49C>T	NP_001029031.1:p.Leu17Phe	missense
NM_001270447.2:c.132-89C>T		intron variant
NM_001270448.2:c.-255C>T		5 prime UTR
NM_001321074.1:c.-1184G>A		5 prime UTR
NM_001365.4:c.-1184G>A
NR_135527.1:n.18G>A		non-coding transcript variant
NC_000017.11:g.7220033C>T
NC_000017.10:g.7123352C>T
NG_007975.1:g.5200C>T
NG_008391.2:g.5018G>A
NG_008391.3:g.5017G>A
NG_194534.1:g.72C>T
	P49748:p.Leu17Phe

... more HGVS ... less HGVS

Protein change

L17F

Other names

NM_000018.4(ACADVL):c.49C>T

Canonical SPDI

NC_000017.11:7220032:C:T

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.

0.02117 (T)

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

The Genome Aggregation Database (gnomAD), exomes 0.00512

Exome Aggregation Consortium (ExAC) 0.00717

The Genome Aggregation Database (gnomAD) 0.02069

1000 Genomes Project 0.02117

Trans-Omics for Precision Medicine (TOPMed) 0.02165

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.02180

1000 Genomes Project 30x 0.02295

Links

ClinGen: CA341522 UniProtKB: P49748#VAR_029286 dbSNP: rs2230179 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	164	338
ACADVL		-	-	GRCh38 GRCh37	1728	1940

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	Benign (6)	reviewed by expert panel	Sep 22, 2022	RCV000020078.31
not specified	Benign (2)	criteria provided, multiple submitters, no conflicts	Mar 30, 2016	RCV000251701.18
not provided	Benign (5)	criteria provided, multiple submitters, no conflicts	Nov 3, 2017	RCV000224359.22

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.
Benign (Sep 22, 2022)	reviewed by expert panel (clingen acadvl acmg specifications v1) Method: curation	Very long chain acyl-CoA dehydrogenase deficiency (Autosomal recessive inheritance) Affected status: unknown Allele origin: germline	ClinGen ACADVL Variant Curation Expert Panel, ClinGen FDA Recognized Database Accession: SCV002576797.2 First in ClinVar: Oct 08, 2022 Last updated: Apr 23, 2023	Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/8cb4ff32-8a03-4e0b-a3f1-75c3222ef92b Comment: The c.49C>T variant in ACADVL has been reported as part of premature screening panels, however no probands have shown increased VLCAD activity or newborn screening … (more) The c.49C>T variant in ACADVL has been reported as part of premature screening panels, however no probands have shown increased VLCAD activity or newborn screening (PMID: 23480858). The highest population minor allele frequency in gnomAD v2.1.1 is 0.06989 in the African population, which is higher than the ClinGen ACADVL Variant Curation Expert Panel threshold (≥0.007) for BA1, and therefore meets this criterion (BA1). The computational predictor REVEL gives a score of 0.236, which is below the threshold of 0.5, evidence that does not predict a damaging effect on ACADVL function (BP4). In summary, this variant meets criteria to be classified as benign for very long chain acyl-CoA dehydrogenase deficiency in an autosomal recessive manner. ACADVL-specific ACMG/AMP criteria applied: BA1; BP4 (less)
Benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	NOT SPECIFIED Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV000301525.1 First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016
Benign (Nov 03, 2017)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process) Method: clinical testing	Not Provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV000602358.2 First in ClinVar: Dec 06, 2016 Last updated: Feb 17, 2019
Benign (Jan 13, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Very long chain acyl-CoA dehydrogenase deficiency Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000406304.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less)
Benign (Feb 01, 2024)	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: SCV000654954.8 First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024
Benign (May 14, 2015)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics Accession: SCV000281019.1 First in ClinVar: Jun 08, 2016 Last updated: Jun 08, 2016
Benign (Mar 08, 2016)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000693965.1 First in ClinVar: Jun 08, 2016 Last updated: Jun 08, 2016	Publications: PubMed (1) PubMed: 23480858 Comment: Variant summary: c.49C>T affects a non-conserved nucleotide, resulting in amino acid change from Leu to Phe. 4/4 in-silico tools predict this variant to be benign … (more) Variant summary: c.49C>T affects a non-conserved nucleotide, resulting in amino acid change from Leu to Phe. 4/4 in-silico tools predict this variant to be benign .The variant was observed in the large and broad control population from ExAC with an allele frequency of 0.0071727% (648/90342 chromosomes) which includes 20 homozygous occurrences. The variant is particularly more common in African population with an allele frequency of 8.8% (597/6748 chromosomes) including 20 homozygotes. This frequency exceeds the maximal expected frequency of a pathogenic allele (0.288%) in this gene, suggesting this variant is benign polymorphism found mainly in African population. One reputable database and a clinical lab classify the variant as benign. Taken together, this variant has been classified as Benign. (less)
Benign (Mar 30, 2016)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000330995.4 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ACADVL Number of individuals with the variant: 5 Zygosity: Homozygote, Single Heterozygote Sex: mixed
Benign (Nov 01, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Very long chain acyl-CoA dehydrogenase deficiency Affected status: unknown Allele origin: germline	Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine Accession: SCV001365171.2 First in ClinVar: Jul 11, 2020 Last updated: Jul 11, 2020	Comment: The NM_000018.3:c.49C>T (NP_000009.1:p.Leu17Phe) [GRCH38: NC_000017.11:g.7220033C>T] variant in ACADVL gene is interpretated to be Benign based on ACMG guidelines (PMID: 25741868). This variant has been reported. … (more) The NM_000018.3:c.49C>T (NP_000009.1:p.Leu17Phe) [GRCH38: NC_000017.11:g.7220033C>T] variant in ACADVL gene is interpretated to be Benign based on ACMG guidelines (PMID: 25741868). This variant has been reported. This variant meets the following evidence codes reported in the ACMG guidelines: BS1, BS2 (less)
Benign (Mar 03, 2015)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001893876.1 First in ClinVar: Sep 19, 2021 Last updated: Sep 19, 2021
Benign (Dec 15, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Very long chain acyl-CoA dehydrogenase deficiency Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002809078.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	not provided (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005255480.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024
Benign (Sep 16, 2020)	no assertion criteria provided Method: clinical testing	Very long chain acyl-CoA dehydrogenase deficiency Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001455117.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021
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Comment:

The c.49C>T variant in ACADVL has been reported as part of premature screening panels, however no probands have shown increased VLCAD activity or newborn screening (PMID: 23480858). The highest population minor allele frequency in gnomAD v2.1.1 is 0.06989 in the African population, which is higher than the ClinGen ACADVL Variant Curation Expert Panel threshold (≥0.007) for BA1, and therefore meets this criterion (BA1). The computational predictor REVEL gives a score of 0.236, which is below the threshold of 0.5, evidence that does not predict a damaging effect on ACADVL function (BP4). In summary, this variant meets criteria to be classified as benign for very long chain acyl-CoA dehydrogenase deficiency in an autosomal recessive manner. ACADVL-specific ACMG/AMP criteria applied: BA1; BP4

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Comment:

Variant summary: c.49C>T affects a non-conserved nucleotide, resulting in amino acid change from Leu to Phe. 4/4 in-silico tools predict this variant to be benign .The variant was observed in the large and broad control population from ExAC with an allele frequency of 0.0071727% (648/90342 chromosomes) which includes 20 homozygous occurrences. The variant is particularly more common in African population with an allele frequency of 8.8% (597/6748 chromosomes) including 20 homozygotes. This frequency exceeds the maximal expected frequency of a pathogenic allele (0.288%) in this gene, suggesting this variant is benign polymorphism found mainly in African population. One reputable database and a clinical lab classify the variant as benign. Taken together, this variant has been classified as Benign.

Comment:

The NM_000018.3:c.49C>T (NP_000009.1:p.Leu17Phe) [GRCH38: NC_000017.11:g.7220033C>T] variant in ACADVL gene is interpretated to be Benign based on ACMG guidelines (PMID: 25741868). This variant has been reported. This variant meets the following evidence codes reported in the ACMG guidelines: BS1, BS2

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
Molecular and cellular pathology of very-long-chain acyl-CoA dehydrogenase deficiency.	Schiff M	Molecular genetics and metabolism	2013	PMID: 23480858
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ACADVL	-	-	-	-
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/8cb4ff32-8a03-4e0b-a3f1-75c3222ef92b	-	-	-	-

Text-mined citations for rs2230179 ...

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 Dec 22, 2024

ClinVar Genomic variation as it relates to human health

NM_000018.4(ACADVL):c.49C>T (p.Leu17Phe)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs2230179 ...