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NM_000018.4(ACADVL):c.521T>C (p.Val174Ala) AND Very long chain acyl-CoA dehydrogenase deficiency

Germline classification:
Uncertain significance (2 submissions)
Last evaluated:
Feb 27, 2024
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:
RCV001200736.2

Allele description [Variation Report for NM_000018.4(ACADVL):c.521T>C (p.Val174Ala)]

NM_000018.4(ACADVL):c.521T>C (p.Val174Ala)

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.521T>C (p.Val174Ala)
Other names:
NM_000018.4(ACADVL):c.521T>C; p.Val174Ala
HGVS:
  • NC_000017.11:g.7221581T>C
  • NG_007975.1:g.6748T>C
  • NG_008391.2:g.3470A>G
  • NM_000018.4:c.521T>CMANE SELECT
  • NM_001033859.3:c.455T>C
  • NM_001270447.2:c.590T>C
  • NM_001270448.2:c.293T>C
  • NP_000009.1:p.Val174Ala
  • NP_001029031.1:p.Val152Ala
  • NP_001257376.1:p.Val197Ala
  • NP_001257377.1:p.Val98Ala
  • NP_001257377.1:p.Val98Ala
  • NC_000017.10:g.7124900T>C
  • NM_000018.3:c.521T>C
  • NM_001270448.1:c.293T>C
Protein change:
V152A
Links:
dbSNP: rs372684079
NCBI 1000 Genomes Browser:
rs372684079
Molecular consequence:
  • NM_000018.4:c.521T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001033859.3:c.455T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001270447.2:c.590T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001270448.2:c.293T>C - missense variant - [Sequence Ontology: SO:0001583]

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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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV001365029Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine
criteria provided, single submitter

(ACMG Guidelines, 2015)		Likely pathogenic
(Nov 1, 2019) 		germlineclinical testing

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

SCV004805223ClinGen ACADVL Variant Curation Expert Panel, ClinGen
reviewed by expert panel

(clingen acadvl acmg specifications v1)		Uncertain Significance
(Feb 27, 2024) 		germlinecuration

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing, curation

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Details of each submission

From Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine, SCV001365029.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

The NM_000018.3:c.521T>C (NP_000009.1:p.Val174Ala) [GRCH38: NC_000017.11:g.7221581T>C] variant in ACADVL gene is interpretated to be Likely Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported. This variant meets the following evidence codes reported in the ACMG guidelines: PM1, PM5, PP3, PP4

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From ClinGen ACADVL Variant Curation Expert Panel, ClinGen, SCV004805223.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

The NM_000018.4: c.521T>C (p.Val174Ala) in ACADVL is a missense variant predicted to cause substitution of valine by alanine at amino acid 174 (p.Val174Ala). The highest population minor allele frequency in GnomAD v4.0.0 is 0.0001 in African/African American population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). This variant has been reported in the literature in an individual with an abnormal newborn screen who is an apparently heterozygous carrier for the variant (PMID: 24503138), but this information is insufficient to use toward classification. The computational predictor REVEL gives a score of 0.926, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). Due to limited evidence, this variant is classified as a variant of uncertain significance 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: PM2_Supporting, PP3 (ACADVL VCEP specifications version 1; approved November 9, 2021).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jun 23, 2024