NM_000018.4(ACADVL):c.1193_1194insGCA (p.Tyr398Ter) AND Very long chain acyl-CoA dehydrogenase deficiency

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Dec 14, 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:: RCV001200808.2

Allele description [Variation Report for NM_000018.4(ACADVL):c.1193_1194insGCA (p.Tyr398Ter)]

NM_000018.4(ACADVL):c.1193_1194insGCA (p.Tyr398Ter)

Gene:

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

Variant type:

Insertion

Cytogenetic location:

17p13.1

Genomic location:

Preferred name:

NM_000018.4(ACADVL):c.1193_1194insGCA (p.Tyr398Ter)

Other names:

NM_000018.4(ACADVL):c.1193_1194insGCA; p.Tyr398Ter

HGVS:

NC_000017.11:g.7223654_7223655insGCA
NG_007975.1:g.8821_8822insGCA
NG_008391.2:g.1397_1398insGCT
NG_033038.1:g.15891_15892insGCT
NM_000018.4:c.1193_1194insGCAMANE SELECT
NM_001033859.3:c.1127_1128insGCA
NM_001270447.2:c.1262_1263insGCA
NM_001270448.2:c.965_966insGCA
NP_000009.1:p.Tyr398Ter
NP_001029031.1:p.Tyr376Ter
NP_001257376.1:p.Tyr421Ter
NP_001257377.1:p.Tyr322Ter
NC_000017.10:g.7126973_7126974insGCA
NM_000018.3:c.1193_1194insGCA

Protein change:

Y322*

Links:

dbSNP: rs2071337202

NCBI 1000 Genomes Browser:

rs2071337202

Molecular consequence:

NM_000018.4:c.1193_1194insGCA - nonsense - [Sequence Ontology: SO:0001587]
NM_001033859.3:c.1127_1128insGCA - nonsense - [Sequence Ontology: SO:0001587]
NM_001270447.2:c.1262_1263insGCA - nonsense - [Sequence Ontology: SO:0001587]
NM_001270448.2:c.965_966insGCA - nonsense - [Sequence Ontology: SO:0001587]

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
SCV001364975	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 (1) [See all records that cite this PMID]
SCV004176818	ClinGen ACADVL Variant Curation Expert Panel, ClinGen	reviewed by expert panel (clingen acadvl acmg specifications v1)	Pathogenic (Dec 14, 2022)	germline	curation	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001364975

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

SCV004176818

ClinGen ACADVL Variant Curation Expert Panel, ClinGen

reviewed by expert panel

(clingen acadvl acmg specifications v1)

Pathogenic
(Dec 14, 2022)

germline

curation

Citation Link

Help

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, 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, SCV001364975.2

#	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.1193_1194insGCA (NP_000009.1:p.Tyr398Ter) [GRCH38: NC_000017.11:g.7223654_7223655insGCA] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported. 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 ClinGen ACADVL Variant Curation Expert Panel, ClinGen, SCV004176818.1

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

Description

The c.1193_1194insGCA; (p.Tyr398delinsTer) variant in ACADVL is a insertion variant predicted to cause an immediate premature stop codon in biologically-relevant-exon 12/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMIDs 9973285, 11590124). At least one individual with this variant was identified by newborn screen, but this information is insufficient to use toward classification (PMID: 26385305). The same amino acid change (p.Tyr398Ter), resulting from a different nucleotide change (c.1194C>A), is classified as pathogenic for very long chain acyl CoA dehydrogenase (VLCAD) deficiency by the ClinGen ACADVL Variant Curation Expert Panel (PS1; PMID: 10529389, ClinVar ID: 810875). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as 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: PVS1, PS1, PM2_Supporting (ACADVL VCEP specifications version 1; approved November 8, 2021).

#	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: Dec 30, 2023

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