rs750653177

Positions:

• chr17-7220827-C-A
• chr17-7220827-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PP4_Moderate PM2_Supporting PM3

This summary comes from the ClinGen Evidence Repository: The c.339C>A variant in ACADVL is a missense variant predicted to cause substitution of phenylalanine by leucine at amino acid 113 (p.(Phe113Leu)). The variant has been identified in at least one individual identified by newborn screen for very long chain acyl CoA dehydrogenase (VLCAD) deficiency with a distinct pathogenic variant and was confirmed in trans by parental testing (PM3 points = 1.0; PMID:21932095; c.848T>C, p.(Val243Ala) ClinVar Variation ID: 21025) (PM3). This individual had NBS C14:1 levels (1.10 uM) above the threshold of ≥ 1.0 μM as specified by the ClinGen ACADVL VCEP. Determination of residual VLCAD activity was performed in lymphocytes derived from this individual and these cells retained 22% ACADVL activity (PMID:21932095) (PP4_Moderate). This variant is absent from gnomAD 2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.722 which is less than the threshold of 0.75 recommended by ClinGen ACADVL VCEP. In summary, this variant meets the criteria to be classified as 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: PM3, PP4_Moderate, PM2_Supporting (ClinGen ACADVL VCEP specifications version #1.0; approved 2022-12-13) LINK:https://erepo.genome.network/evrepo/ui/classification/CA397722617/MONDO:0008723/021

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ACADVL NM_000018.4 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:2 U:1
• Conservation: PhyloP100: -0.789

Genes affected

ACADVL (HGNC:92): (acyl-CoA dehydrogenase very long chain) The protein encoded by this gene is targeted to the inner mitochondrial membrane where it catalyzes the first step of the mitochondrial fatty acid beta-oxidation pathway. This acyl-Coenzyme A dehydrogenase is specific to long-chain and very-long-chain fatty acids. A deficiency in this gene product reduces myocardial fatty acid beta-oxidation and is associated with cardiomyopathy. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

ACADVL (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACADVL	NM_000018.4	c.339C>A	p.Phe113Leu	missense_variant	5/20	ENST00000356839.10	NP_000009.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACADVL	ENST00000356839.10	c.339C>A	p.Phe113Leu	missense_variant	5/20	1	NM_000018.4	ENSP00000349297.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461754 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727160

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Very long chain acyl-CoA dehydrogenase deficiency Pathogenic:2 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	Nov 01, 2019	The NM_000018.3:c.339C>A (NP_000009.1:p.Phe113Leu) [GRCH38: NC_000017.11:g.7220827C>A] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 21932095. This variant meets the following evidence codes reported in the ACMG guidelines: PS1, PS3 -
Uncertain significance, reviewed by expert panel	curation	ClinGen ACADVL Variant Curation Expert Panel, ClinGen	Dec 13, 2022	The c.339C>A variant in ACADVL is a missense variant predicted to cause substitution of phenylalanine by leucine at amino acid 113 (p.(Phe113Leu)). The variant has been identified in at least one individual identified by newborn screen for very long chain acyl CoA dehydrogenase (VLCAD) deficiency with a distinct pathogenic variant and was confirmed in trans by parental testing (PM3 points = 1.0; PMID: 21932095; c.848T>C, p.(Val243Ala) ClinVar Variation ID: 21025) (PM3). This individual had NBS C14:1 levels (1.10 uM) above the threshold of ≥ 1.0 μM as specified by the ClinGen ACADVL VCEP. Determination of residual VLCAD activity was performed in lymphocytes derived from this individual and these cells retained 22% ACADVL activity (PMID: 21932095) (PP4_Moderate). This variant is absent from gnomAD 2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.722 which is less than the threshold of 0.75 recommended by ClinGen ACADVL VCEP. In summary, this variant meets the criteria to be classified as 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: PM3, PP4_Moderate, PM2_Supporting (ClinGen ACADVL VCEP specifications version #1.0; approved 2022-12-13) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 30, 2019	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed in individual(s) with very longchain acyl-CoA dehydrogenase deficiency (PMID: 21932095, 30194637). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 474895). This variant is not present in population databases (ExAC no frequency). This sequence change replaces phenylalanine with leucine at codon 113 of the ACADVL protein (p.Phe113Leu). The phenylalanine residue is highly conserved and there is a small physicochemical difference between phenylalanine and leucine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.88	.;D;.;.;.
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.63	D
LIST_S2	Uncertain	0.91	D;D;D;D;T
M_CAP	Pathogenic	0.74	D
MetaRNN	Pathogenic	0.80	D;D;D;D;D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Benign	1.5	.;L;.;.;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-5.3	D;.;.;D;.
REVEL	Pathogenic	0.72
Sift	Benign	0.098	T;.;.;T;.
Sift4G	Benign	0.18	T;T;T;T;D
Polyphen		1.0, 0.81	.;D;.;P;.
Vest4		0.84
MutPred		0.52		.;Loss of glycosylation at S110 (P = 0.096);Loss of glycosylation at S110 (P = 0.096);.;Loss of glycosylation at S110 (P = 0.096);
MVP		0.92
MPC		0.26
ClinPred		0.99	D
GERP RS		-3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.86
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs750653177; hg19: chr17-7124146;