Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

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Variant: NM_000018.4(ACADVL):c.1679-6G>A

CA312281

21019 (ClinVar)

Gene: ACADVL

Condition: very long chain acyl-CoA dehydrogenase deficiency

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 42f2d324-a5ae-4dcb-aa3e-b606dc669fe5

HGVS expressions

NM_000018.4:c.1679-6G>A

NM_000018.4(ACADVL):c.1679-6G>A

NC_000017.11:g.7224636G>A

CM000679.2:g.7224636G>A

NC_000017.10:g.7127955G>A

CM000679.1:g.7127955G>A

NC_000017.9:g.7068679G>A

NG_007975.1:g.9803G>A

NG_008391.2:g.415C>T

NG_033038.1:g.14909C>T

ENST00000356839.10:c.1679-6G>A

ENST00000322910.9:c.*1634-6G>A

ENST00000350303.9:c.1613-6G>A

ENST00000356839.9:c.1679-6G>A

ENST00000542255.6:n.537-79G>A

ENST00000543245.6:c.1748-6G>A

ENST00000578033.1:n.4G>A

ENST00000578319.5:n.260-6G>A

ENST00000578711.1:n.1132G>A

ENST00000578809.5:n.251-6G>A

ENST00000579425.5:n.795-6G>A

ENST00000579546.1:n.414-6G>A

ENST00000582450.1:n.270G>A

ENST00000583074.5:n.300-79G>A

ENST00000583848.5:n.65-26G>A

ENST00000583850.5:n.450-6G>A

ENST00000583858.5:n.610-6G>A

ENST00000585203.6:n.870-6G>A

NM_000018.3:c.1679-6G>A

NM_001033859.2:c.1613-6G>A

NM_001270447.1:c.1748-6G>A

NM_001270448.1:c.1451-6G>A

NM_001033859.3:c.1613-6G>A

NM_001270447.2:c.1748-6G>A

NM_001270448.2:c.1451-6G>A

Likely Pathogenic

PP4_Moderate PS3_Supporting PM2_Supporting PM3_Strong

PP3

Evidence Links 1

Expert Panel

ACADVL VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

ACADVL VCEP

The c.1679-6G>A variant in ACADVL is an intronic variant which creates a novel acceptor site in intron 17, experimentally shown to cause insertion of four nucleotides and causes a frameshift (PS3_Supporting; PMID: 9709714). This variant has been reported in several individuals affected with very long chain acyl CoA dehydrogenase (VLCAD) deficiency confirmed in trans to at least one pathogenic variant, presumed in trans to distinct ACADVL variants, and in the homozygous state in at least two individuals (PM3_Strong; PMIDs:23480858, 9709714, 8845838). Fibroblasts derived from one of these individuals showed no detectable VLCAD activity, which is highly specific for VLCAD deficiency (PP4_Moderate; PMID: 234808). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0002264 in the Latino/Admixed American population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PS3_Supporting, PM3_Strong, PM2_Supporting, PP4_Moderate (ACADVL VCEP specifications version 1; approved November 8, 2021).

PP4_Moderate

No detectable VLCAD activity in fibroblasts from this patient 11 in PMID 234808, plasma acylcarnitine profile consistent with VLCAD

PS3_Supporting

Creation of a novel acceptor, insertion of four nucleotides, causing a frameshift.

RT-PCR of patient DNA showed that this creates a novel acceptor, insertion of four nucleotides. PubMed:9709714

PM2_Supporting

The highest population minor allele frequency in gnomAD v2.1.1 is 0.0002264 in the Latino/Admixed American population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting).

PM3_Strong

Described in the homozygous state in two individuals and confirmed in trans by cloning to F458L (now in review by VCEP)

PP3

SpliceAI gives a score of 0.99 for creation of a novel acceptor; however, not counted due to "double dipping" of this and PS3_Supporting showing the novel acceptor is used and a frameshift is created.

Approved on: 2022-12-14

Published on: 2022-12-14

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