NM_000018.4:c.619T>C

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM3_StrongPP4_ModeratePM2PP3

This summary comes from the ClinGen Evidence Repository: The NM_000018.4(ACADVL): c.619T>C (p.Ser207Pro) variant is a missense variant predicted to cause substitution of serine by proline at amino acid 207. At least two individuals with this variant displayed a newborn screen consistent with very long chain acyl-CoA dehydrogenase (VLCAD) deficiency as well as follow-up acylcarnitine testing showing increased C14:1 acylcarnitines, which is highly specific for VLCAD deficiency (PP4_Moderate, PMID:26927351). This individual was compound heterozygous for this variant and a distinct pathogenic or likely pathogenic variant confirmed in trans by parental testing (PM3_Strong). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.79, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). 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: PM2_Supporting, PM3_Strong, PP3, PP4_Moderate (ACADVL VCEP specifications version 1; approved November 9, 2021). LINK:https://erepo.genome.network/evrepo/ui/classification/CA8337769/MONDO:0008723/021

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

ACADVL
NM_000018.4 missense

Scores

Clinical Significance

Likely pathogenic reviewed by expert panel P:3U:3

Conservation

PhyloP100: 0.361

Publications

2 publications found

Variant links:

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 Gene-Disease associations (from GenCC):

very long chain acyl-CoA dehydrogenase deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, ClinGen, PanelApp Australia, Labcorp Genetics (formerly Invitae)

ACADVL links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 9 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.

PP3

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 rank	MANE	Protein	UniProt
ACADVL	NM_000018.4 link	c.619T>C	p.Ser207Pro	missense_variant	Exon 7 of 20	ENST00000356839.10	NP_000009.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACADVL	ENST00000356839.10 link	c.619T>C	p.Ser207Pro	missense_variant	Exon 7 of 20	1	NM_000018.4	ENSP00000349297.5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000239

AC:

AN:

251078

AF XY:

0.0000147

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000326

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000411

AC:

AN:

1461470

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727036

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.000126

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53016

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112008

Other (OTH)

AF:

0.00

AC:

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3Uncertain:3

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Very long chain acyl-CoA dehydrogenase deficiency

Pathogenic:3Uncertain:3

Jun 09, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The ACADVL c.619T>C; p.Ser207Pro variant (rs768975918) is reported in the literature in two individuals affected with VLCAD deficiency (Ko 2016). This variant is also reported in ClinVar (Variation ID: 551588). This variant is found in the East Asian population with an allele frequency of 0.03% (6/18390 alleles) in the Genome Aggregation Database. The serine at codon 207 is moderately conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.792). However, given the lack of clinical and functional data, the significance of the p.Ser207Pro variant is uncertain at this time. References: Ko JM et al. Rare Korean Cases of Very-long-chain Acyl-CoA Dehydrogenase Deficiency with a Novel Recurrent Mutation. Ann Clin Lab Sci. 2016 Winter;46(1):97-101. PMID: 26927351. -

Feb 27, 2024

ClinGen ACADVL Variant Curation Expert Panel, ClinGen

Significance:Likely pathogenic

Review Status:reviewed by expert panel

Collection Method:curation

The NM_000018.4(ACADVL): c.619T>C (p.Ser207Pro) variant is a missense variant predicted to cause substitution of serine by proline at amino acid 207. At least two individuals with this variant displayed a newborn screen consistent with very long chain acyl-CoA dehydrogenase (VLCAD) deficiency as well as follow-up acylcarnitine testing showing increased C14:1 acylcarnitines, which is highly specific for VLCAD deficiency (PP4_Moderate, PMID: 26927351). This individual was compound heterozygous for this variant and a distinct pathogenic or likely pathogenic variant confirmed in trans by parental testing (PM3_Strong). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.79, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). 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: PM2_Supporting, PM3_Strong, PP3, PP4_Moderate (ACADVL VCEP specifications version 1; approved November 9, 2021). -

Apr 19, 2017

Counsyl

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Mar 08, 2024

Baylor Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 24, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 207 of the ACADVL protein (p.Ser207Pro). This variant is present in population databases (rs768975918, gnomAD 0.03%). This missense change has been observed in individual(s) with very long chain acyl-CoA dehydrogenase deficiency (PMID: 26385305, 26927351; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 551588). 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. -

Nov 01, 2019

Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The NM_000018.3:c.619T>C (NP_000009.1:p.Ser207Pro) [GRCH38: NC_000017.11:g.7221679T>C] variant in ACADVL gene is interpretated to be Uncertain Significance based on ACMG guidelines (PMID: 25741868). This variant has been reported. This variant meets the following evidence codes reported in the ACMG guidelines: PM1, PP3 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.67

BayesDel_addAF

Uncertain

0.067

BayesDel_noAF

Pathogenic

0.16

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.95

.;D;.;.;D

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.93

D;D;T;D;D

M_CAP

Pathogenic

0.88

MetaRNN

Uncertain

0.74

D;D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.2

.;H;.;.;.

PhyloP100

0.36

PrimateAI

Benign

0.43

PROVEAN

Uncertain

-3.4

D;.;.;D;.

REVEL

Pathogenic

0.79

Sift

Uncertain

0.0020

D;.;.;D;.

Sift4G

Uncertain

0.0040

D;D;D;D;D

Polyphen

0.99, 0.92

.;D;.;P;.

Vest4

0.85

MutPred

0.54

.;Gain of methylation at K204 (P = 0.1095);Gain of methylation at K204 (P = 0.1095);.;.;

MVP

0.99

MPC

0.74

ClinPred

0.97

GERP RS

2.2

Varity_R

0.93

gMVP

0.84

Mutation Taster

=9/91

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over