NM_000018.4(ACADVL):c.1220G>C (p.Gly407Ala) AND Very long chain acyl-CoA dehydrogenase deficiency

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: Feb 12, 2020)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
3 submissions [Details]
Record status:
current
Accession:
RCV000544920.5

Allele description [Variation Report for NM_000018.4(ACADVL):c.1220G>C (p.Gly407Ala)]

NM_000018.4(ACADVL):c.1220G>C (p.Gly407Ala)

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.1220G>C (p.Gly407Ala)
HGVS:
  • NC_000017.11:g.7223681G>C
  • NG_007975.1:g.8848G>C
  • NG_008391.2:g.1370C>G
  • NG_033038.1:g.15864C>G
  • NM_000018.4:c.1220G>CMANE SELECT
  • NM_001033859.2:c.1154G>C
  • NM_001270447.1:c.1289G>C
  • NM_001270448.1:c.992G>C
  • NP_000009.1:p.Gly407Ala
  • NP_001029031.1:p.Gly385Ala
  • NP_001257376.1:p.Gly430Ala
  • NP_001257377.1:p.Gly331Ala
  • NC_000017.10:g.7127000G>C
  • NM_000018.2:c.1220G>C
  • NM_000018.3:c.1220G>C
Protein change:
G331A
Links:
dbSNP: rs904631654
NCBI 1000 Genomes Browser:
rs904631654
Molecular consequence:
  • NM_000018.4:c.1220G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001033859.2:c.1154G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001270447.1:c.1289G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001270448.1:c.992G>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000654920Invitaecriteria provided, single submitter
Pathogenic
(Feb 12, 2020)
germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV001365088Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicinecriteria provided, single submitter
Likely pathogenic
(Nov 1, 2019)
germlineclinical testing

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

SCV001459251Natera, Inc.no assertion criteria providedUncertain significance
(Sep 16, 2020)
germlineclinical testing

Summary from all submissions

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

Citations

PubMed

Four Years' Experience in the Diagnosis of Very Long-Chain Acyl-CoA Dehydrogenase Deficiency in Infants Detected in Three Spanish Newborn Screening Centers.

Merinero B, Alcaide P, Martín-Hernández E, Morais A, García-Silva MT, Quijada-Fraile P, Pedrón-Giner C, Dulin E, Yahyaoui R, Egea JM, Belanger-Quintana A, Blasco-Alonso J, Fernandez Ruano ML, Besga B, Ferrer-López I, Leal F, Ugarte M, Ruiz-Sala P, Pérez B, Pérez-Cerdá C.

JIMD Rep. 2018;39:63-74. doi: 10.1007/8904_2017_40. Epub 2017 Jul 29.

PubMed [citation]
PMID:
28755359
PMCID:
PMC5953901

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
See all PubMed Citations (3)

Details of each submission

From Invitae, SCV000654920.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

This sequence change replaces glycine with alanine at codon 407 of the ACADVL protein (p.Gly407Ala). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and alanine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with VLCAD deficiency in a family (PMID: 28755359) and has also been observed in an individual with VLCAD deficiency (Invitae). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. For these reasons, this variant has been classified as Pathogenic.

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

From Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine, SCV001365088.2

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

Description

The NM_000018.3:c.1220G>C (NP_000009.1:p.Gly407Ala) [GRCH38: NC_000017.11:g.7223681G>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, PM3, PP3, PP4

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

From Natera, Inc., SCV001459251.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 6, 2021

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