NM_000018.4(ACADVL):c.1894C>T (p.Arg632Cys) AND Very long chain acyl-CoA dehydrogenase deficiency

Germline classification:: Uncertain significance (6 submissions)
Last evaluated:: Jan 31, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000525816.20

Allele description [Variation Report for NM_000018.4(ACADVL):c.1894C>T (p.Arg632Cys)]

NM_000018.4(ACADVL):c.1894C>T (p.Arg632Cys)

Gene:

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

Variant type:

single nucleotide variant

Cytogenetic location:

17p13.1

Genomic location:

Preferred name:

NM_000018.4(ACADVL):c.1894C>T (p.Arg632Cys)

HGVS:

NC_000017.11:g.7225023C>T
NG_007975.1:g.10190C>T
NG_008391.2:g.28G>A
NG_033038.1:g.14522G>A
NM_000018.4:c.1894C>TMANE SELECT
NM_001033859.3:c.1828C>T
NM_001270447.2:c.1963C>T
NM_001270448.2:c.1666C>T
NP_000009.1:p.Arg632Cys
NP_001029031.1:p.Arg610Cys
NP_001257376.1:p.Arg655Cys
NP_001257377.1:p.Arg556Cys
NC_000017.10:g.7128342C>T
NM_000018.2:c.1894C>T
NM_000018.3:c.1894C>T

Protein change:

R556C

Links:

dbSNP: rs151254520

NCBI 1000 Genomes Browser:

rs151254520

Molecular consequence:

NM_000018.4:c.1894C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001033859.3:c.1828C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001270447.2:c.1963C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001270448.2:c.1666C>T - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000654947	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 31, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 27209629, 28492532
SCV000788720	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Uncertain significance (Jan 6, 2017)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 27209629, 26385305 Citation Link,
SCV001365218	Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Nov 1, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002088825	Natera, Inc.	no assertion criteria provided	Uncertain significance (Feb 18, 2020)	germline	clinical testing
SCV002548727	New York Genome Center - CSER-NYCKidSeq	criteria provided, single submitter (NYGC Assertion Criteria 2020)	Uncertain significance (Jul 16, 2021)	inherited	clinical testing	Citation Link

Help

Summary from all submissions

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

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Outcomes and genotype-phenotype correlations in 52 individuals with VLCAD deficiency diagnosed by NBS and enrolled in the IBEM-IS database.

Pena LD, van Calcar SC, Hansen J, Edick MJ, Walsh Vockley C, Leslie N, Cameron C, Mohsen AW, Berry SA, Arnold GL, Vockley J; IBEMC..

Mol Genet Metab. 2016 Aug;118(4):272-81. doi: 10.1016/j.ymgme.2016.05.007. Epub 2016 May 13.

PubMed [citation]

PMID:: 27209629
PMCID:: PMC4970910

See all PubMed Citations (4)

Details of each submission

From Invitae, SCV000654947.9

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

Description

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 632 of the ACADVL protein (p.Arg632Cys). This variant is present in population databases (rs151254520, gnomAD 0.07%). This missense change has been observed in individual(s) with very long-chain acyl-CoA dehydrogenase deficiency (PMID: 27209629). ClinVar contains an entry for this variant (Variation ID: 474894). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ACADVL protein function with a positive predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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 Counsyl, SCV000788720.1

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

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

From Baylor Genetics, SCV001163429.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	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	unknown	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, SCV001365218.2

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

Description

The NM_000018.3:c.1894C>T (NP_000009.1:p.Arg632Cys) [GRCH38: NC_000017.11:g.7225023C>T] variant in ACADVL gene is interpretated to be Uncertain Significance based on ACMG guidelines (PMID: 25741868). This variant has been reported. This variant meets the following evidence codes reported in the ACMG guidelines: PP3

#	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 Natera, Inc., SCV002088825.1

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

#	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 New York Genome Center - CSER-NYCKidSeq, SCV002548727.1

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

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

Flagged submissions

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001163429	Baylor Genetics	flagged submission Reason: Outlier claim with insufficient supporting evidence Notes: None (ACMG Guidelines, 2015)	Likely pathogenic (Jan 20, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001163429

Baylor Genetics

flagged submission

Reason: Outlier claim with insufficient supporting evidence

Notes: None

(ACMG Guidelines, 2015)

Likely pathogenic
(Jan 20, 2021)

unknown

clinical testing

PubMed (1)
[See all records that cite this PMID]

Last Updated: Apr 15, 2024

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