NM_000018.4(ACADVL):c.1001T>G (p.Met334Arg) AND Very long chain acyl-CoA dehydrogenase deficiency

Germline classification:: Conflicting interpretations of pathogenicity (6 submissions)
Last evaluated:: Dec 22, 2023
Review status:: criteria provided, conflicting classifications

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:: RCV000668860.34

Allele description [Variation Report for NM_000018.4(ACADVL):c.1001T>G (p.Met334Arg)]

NM_000018.4(ACADVL):c.1001T>G (p.Met334Arg)

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.1001T>G (p.Met334Arg)

Other names:

p.M334R:ATG>AGG

HGVS:

NC_000017.11:g.7222789T>G
NG_007975.1:g.7956T>G
NG_008391.2:g.2262A>C
NM_000018.4:c.1001T>GMANE SELECT
NM_001033859.3:c.935T>G
NM_001270447.2:c.1070T>G
NM_001270448.2:c.773T>G
NP_000009.1:p.Met334Arg
NP_000009.1:p.Met334Arg
NP_001029031.1:p.Met312Arg
NP_001257376.1:p.Met357Arg
NP_001257377.1:p.Met258Arg
NC_000017.10:g.7126108T>G
NM_000018.2:c.1001T>G
NM_000018.3:c.1001T>G
NM_001033859.1:c.935T>G

Protein change:

M258R

Links:

dbSNP: rs398123079

NCBI 1000 Genomes Browser:

rs398123079

Molecular consequence:

NM_000018.4:c.1001T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001033859.3:c.935T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001270447.2:c.1070T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001270448.2:c.773T>G - 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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000815383	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 6, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 27209629, 28492532
SCV001160513	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2021)	Uncertain significance (Apr 15, 2022)	germline	clinical testing	Citation Link,
SCV001365225	Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Nov 1, 2019)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 26385305, 25741868
SCV002060163	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2021))	Uncertain significance (Oct 27, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV003822472	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Aug 25, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004215114	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Dec 22, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
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. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Recurrent ACADVL molecular findings in individuals with a positive newborn screen for very long chain acyl-coA dehydrogenase (VLCAD) deficiency in the United States.

Miller MJ, Burrage LC, Gibson JB, Strenk ME, Lose EJ, Bick DP, Elsea SH, Sutton VR, Sun Q, Graham BH, Craigen WJ, Zhang VW, Wong LJ.

Mol Genet Metab. 2015 Nov;116(3):139-45. doi: 10.1016/j.ymgme.2015.08.011. Epub 2015 Sep 2.

PubMed [citation]

PMID:: 26385305
PMCID:: PMC4790081

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000815383.6

#	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 methionine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 334 of the ACADVL protein (p.Met334Arg). This variant is present in population databases (rs398123079, gnomAD 0.004%). This missense change has been observed in individual(s) with VLCAD deficiency (PMID: 27209629; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 92270). 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%. 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 ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV001160513.3

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

Description

The ACADVL c.1001T>G; p.Met334Arg variant (rs148584617) is reported in the literature in multiple individuals affected with very long chain acyl-coA dehydrogenase deficiency (Miller 2015, Pena 2016). This variant is reported as uncertain significance by multiple laboratories in ClinVar (Variation ID: 92270), and is only observed on five alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The methionine at codon 334 is moderately conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.945). However, given the lack of clinical and functional data, the significance of the p.Met334Arg variant is uncertain at this time. References: Miller MJ et al. Recurrent ACADVL molecular findings in individuals with a positive newborn screen for very long chain acyl-coA dehydrogenase (VLCAD) deficiency in the United States. Mol Genet Metab. 2015 Nov;116(3):139-45. PMID: 26385305. Pena LD et al. Outcomes and genotype-phenotype correlations in 52 individuals with VLCAD deficiency diagnosed by NBS and enrolled in the IBEM-IS database. Mol Genet Metab. 2016 Aug;118(4):272-81. PMID: 27209629.

#	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, SCV001365225.2

#	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.1001T>G (NP_000009.1:p.Met334Arg) [GRCH38: NC_000017.11:g.7222789T>G] 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: PS3, PM1, 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 Myriad Genetics, Inc., SCV002060163.2

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

Description

NM_000018.3(ACADVL):c.1001T>G(M334R) is a missense variant classified as a variant of uncertain significance in the context of very-long-chain acyl-CoA dehydrogenase deficiency. M334R has been observed in cases with relevant disease (PMID: 27209629). Functional assessments of this variant are not available in the literature. M334R has been observed in population frequency databases (gnomAD: NFE 0.002%). In summary, there is insufficient evidence to classify NM_000018.3(ACADVL):c.1001T>G(M334R) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening.

#	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 Revvity Omics, Revvity, SCV003822472.2

#	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	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV004215114.2

#	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

Last Updated: Oct 13, 2024

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