NM_000018.4(ACADVL):c.1497CCT[1] (p.Leu502del) AND Very long chain acyl-CoA dehydrogenase deficiency

This record was updated by the submitter. Please see the current version.

Germline classification:: Likely pathogenic (4 submissions)
Last evaluated:: Dec 13, 2022
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001059445.10

Allele description

NM_000018.4(ACADVL):c.1497CCT[1] (p.Leu502del)

Gene:

ACADVL:acyl-CoA dehydrogenase very long chain [Gene - OMIM - HGNC]

Variant type:

Microsatellite

Cytogenetic location:

17p13.1

Genomic location:

Preferred name:

NM_000018.4(ACADVL):c.1497CCT[1] (p.Leu502del)

Other names:

NM_000018.4(ACADVL):c.1497CCT[1]; p.Leu502del

HGVS:

NC_000017.11:g.7224208CCT[1]
NC_000017.11:g.7224208_7224210CCT[1]
NG_007975.1:g.9375CCT[1]
NG_008391.2:g.838AGG[1]
NG_033038.1:g.15332AGG[1]
NM_000018.4:c.1497CCT[1]MANE SELECT
NM_001033859.3:c.1431CCT[1]
NM_001270447.2:c.1566CCT[1]
NM_001270448.2:c.1269CCT[1]
NP_000009.1:p.Leu502del
NP_001029031.1:p.Leu480del
NP_001257376.1:p.Leu525del
NP_001257377.1:p.Leu426del
NC_000017.10:g.7127527CCT[1]
NC_000017.10:g.7127527_7127529del
NC_000017.11:g.7224208CCT[1]
NM_000018.3:c.1500_1502del
NM_000018.3:c.1500_1502delCCT
NM_000018.4:c.1500_1502delMANE SELECT

Protein change:

L426del

Links:

dbSNP: rs762619071

NCBI 1000 Genomes Browser:

rs762619071

Molecular consequence:

NM_000018.4:c.1497CCT[1] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001033859.3:c.1431CCT[1] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001270447.2:c.1566CCT[1] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001270448.2:c.1269CCT[1] - inframe_deletion - [Sequence Ontology: SO:0001822]

Observations:

Condition(s)

Name:: Very long chain acyl-CoA dehydrogenase deficiency (ACADVLD)
Synonyms:: VLCAD deficiency
Identifiers:: MONDO: MONDO:0008723; MedGen: C3887523; Orphanet: 26793; OMIM: 201475

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001224069	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 9, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 16488171, 19327992, 24765510, 28492532
SCV001364933	Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 1, 2019)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 16488171, 25741868
SCV002580355	MGZ Medical Genetics Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Sep 29, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002769759	ClinGen ACADVL Variant Curation Expert Panel, ClinGen	reviewed by expert panel (clingen acadvl acmg specifications v1)	Likely pathogenic (Dec 13, 2022)	germline	curation	Citation Link

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, curation

Citations

PubMed

Diagnostic assessment and long-term follow-up of 13 patients with Very Long-Chain Acyl-Coenzyme A dehydrogenase (VLCAD) deficiency.

Laforêt P, Acquaviva-Bourdain C, Rigal O, Brivet M, Penisson-Besnier I, Chabrol B, Chaigne D, Boespflug-Tanguy O, Laroche C, Bedat-Millet AL, Behin A, Delevaux I, Lombès A, Andresen BS, Eymard B, Vianey-Saban C.

Neuromuscul Disord. 2009 May;19(5):324-9. doi: 10.1016/j.nmd.2009.02.007. Epub 2009 Mar 26.

PubMed [citation]

PMID:: 19327992

Rhabdomyolysis as a presenting manifestation of very long-chain acyl-coenzyme a dehydrogenase deficiency.

Oliveira SF, Pinho L, Rocha H, Nogueira C, Vilarinho L, Dinis MJ, Silva C.

Clin Pract. 2013 Aug 2;3(2):e22. doi: 10.4081/cp.2013.e22.

PubMed [citation]

PMID:: 24765510
PMCID:: PMC3981269

See all PubMed Citations (5)

Details of each submission

From Invitae, SCV001224069.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This variant, c.1500_1502del, results in the deletion of 1 amino acid(s) of the ACADVL protein (p.Leu502del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs762619071, gnomAD 0.0009%). This variant has been observed in individual(s) with very long-chain acyl-CoA dehydrogenase deficiency (PMID: 16488171, 19327992, 24765510). It has also been observed to segregate with disease in related individuals. This variant is also known as c.1497_1499delCCT. ClinVar contains an entry for this variant (Variation ID: 854401). For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine, SCV001364933.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

The NM_000018.3:c.1500_1502delCCT (NP_000009.1:p.Leu502del) [GRCH38: NC_000017.11:g.7224211_7224213delCCT] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 16488171. This variant meets the following evidence codes reported in the ACMG guidelines: PVS1, PS3

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From MGZ Medical Genetics Center, SCV002580355.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From ClinGen ACADVL Variant Curation Expert Panel, ClinGen, SCV002769759.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	not provided

Description

The c.1500_1502del variant is predicted to cause a change in the length of the protein (p.Leu502del) due to an in-frame deletion of one amino acid in a non-repeat region (PM4). This variant has been detected in six individuals with very long chain acyl CoA dehydrogenase (VLCAD) deficiency. Of those individuals, one was assumed compound heterozygous for the variant and a distinct pathogenic variant, p.Val243Ala; parental confirmation was not provided (PM3 points=0.5, PMID: 30194637, ClinVar Variation ID: 21025). Five individuals were homozygous for the variant (PM3 points = 1.0 max, PMIDs: 26385305, 27943070, 24765510, 32793418) (Total PM3 points = 1.5; PM3). At least one patient with this variant displayed VLCAD enzyme activity <= 20% of normal which is highly specific for very long chain acyl-CoA dehydrogenase (VLCAD) deficiency (PP4_Moderate, PMIDs: 30194637, 27943070, 32793418). This variant resides within a region, amino acids 481-516: Membrane binding, of ACADVL that is defined as a critical functional domain by the ClinGen ACADVL Variant Curation Expert Panel (PMIDs: 18227065, 20060901) (PM1). The highest population minor allele frequency in gnomAD v2.1.1 is 0.000008795 in Non-Finnish European population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as LIKELY PATHOGENIC for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM3, PP4_Moderate, PM1, PM4, PM2_Supporting. (ClinGen ACADVL VCEP specifications version#1.0; approved 12-13-22)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: May 7, 2024

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