rs749159573

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PP4_ModeratePM3PP3PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000018.4(ACADVL): c.751A>G (p.Ser251Gly) variant is a missense variant predicted to cause substitution of serine by glycine at amino acid 251. This variant has been detected in one individual with very long chain acyl CoA dehydrogenase (VLCAD) deficiency. This individual was compound heterozygous for the variant and a pathogenic variant and confirmed in trans by parental testing (1.0 PM3 points, PMID:26937394, PM3_moderate). At least one patient with this variant displayed NBS C14:1 levels ≥ 1.0 μM and follow-up Plasma Acylcarnitine analysis consistent with VLCADD, which is highly specific for VLCAD deficiency (PP4_moderate, PMID:26937394). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00003 in the non-Finnish European population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.978, 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_moderate, PP3, PP4_Moderate (ACADVL VCEP specifications version 1; approved November 9, 2021). LINK:https://erepo.genome.network/evrepo/ui/classification/CA10640460/MONDO:0008723/021

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

ACADVL
NM_000018.4 missense, splice_region

Scores

Clinical Significance

Likely pathogenic reviewed by expert panel P:4U:4

Conservation

PhyloP100: 8.17

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 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.751A>G	p.Ser251Gly	missense_variant, splice_region_variant	Exon 8 of 20	ENST00000356839.10	NP_000009.1	P49748-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACADVL	ENST00000356839.10 link	c.751A>G	p.Ser251Gly	missense_variant, splice_region_variant	Exon 8 of 20	1	NM_000018.4	ENSP00000349297.5		P49748-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251484

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000752

AC:

AN:

1461868

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

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:

0.00000809

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000789

Hom.:

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4Uncertain:4

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Very long chain acyl-CoA dehydrogenase deficiency

Pathogenic:4Uncertain:3

Jul 01, 2024

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 glycine, which is neutral and non-polar, at codon 251 of the ACADVL protein (p.Ser251Gly). This variant is present in population databases (rs749159573, gnomAD 0.003%). This missense change has been observed in individual(s) with very long chain acyl CoA dehydrogenase deficiency (VLCAD) deficiency confirmed by biochemical assays (PMID: 26937394; 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: 324989). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Nov 18, 2023

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Nov 01, 2019

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NM_000018.3:c.751A>G (NP_000009.1:p.Ser251Gly) [GRCH38: NC_000017.11:g.7222080A>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, PM3, PP3, PP4 -

Nov 03, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ACADVL c.751A>G; p.Ser251Gly (rs749159573) is reported in trans to a pathogenic variant in an infant with VLCAD deficiency (Scott Schwoerer 2015). The variant is reported in the ClinVar database (Variation ID: 324989) and is found in the general population with an overall allele frequency of 0.001% (3/251,484 alleles) in the Genome Aggregation Database. The serine at codon 251 is highly conserved and computational analyses predict that this variant is deleterious (REVEL: 0.978). However, given the lack of clinical and functional data, the significance of the p.Ser251Gly variant is uncertain at this time. References: Scott Schwoerer J et al. Rhabdomyolysis in a neonate due to very long chain acyl CoA dehydrogenase deficiency. Mol Genet Metab Rep. 2015 Mar 30;3:39-41. -

Feb 25, 2025

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.751A>G (p.Ser251Gly) variant is a missense variant predicted to cause substitution of serine by glycine at amino acid 251. This variant has been detected in one individual with very long chain acyl CoA dehydrogenase (VLCAD) deficiency. This individual was compound heterozygous for the variant and a pathogenic variant and confirmed in trans by parental testing (1.0 PM3 points, PMID: 26937394, PM3_moderate). At least one patient with this variant displayed NBS C14:1 levels ≥ 1.0 μM and follow-up Plasma Acylcarnitine analysis consistent with VLCADD, which is highly specific for VLCAD deficiency (PP4_moderate, PMID: 26937394). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00003 in the non-Finnish European population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.978, 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_moderate, PP3, PP4_Moderate (ACADVL VCEP specifications version 1; approved November 9, 2021). -

Nov 19, 2021

Myriad Genetics, Inc.

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NM_000018.3(ACADVL):c.751A>G(S251G) is a missense variant classified as a variant of uncertain significance in the context of very-long-chain acyl-CoA dehydrogenase deficiency. S251G has been observed in cases with relevant disease (PMID: 26385305, 26937394). Functional assessments of this variant are not available in the literature. S251G has been observed in population frequency databases (gnomAD: NFE <0.001%). In summary, there is insufficient evidence to classify NM_000018.3(ACADVL):c.751A>G(S251G) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. -

ACADVL-related disorder

Uncertain:1

Jun 17, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ACADVL c.751A>G variant is predicted to result in the amino acid substitution p.Ser251Gly. This variant has been reported on the opposite allele (i.e., in trans) of a pathogenic ACADVL variant in a single patient with abnormal newborn screening and an episode of rhabdomyolysis concerning for very long chain acyl-CoA dehydrogenase deficiency (VLCADD) (Scott Schwoerer et al. 2015. PubMed ID: 26937394). However, we have also observed this variant at PreventionGenetics, in the heterozygous state without a second variant identified, in two patients with suspected VLCADD. This variant is reported in 0.0026% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpret as uncertain significance, likely pathogenic and pathogenic in Clinvar (https://www.ncbi.nlm.nih.gov/clinvar/variation/324989/). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.83

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Pathogenic

0.46

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.93

.;D;.

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

D;D;D

M_CAP

Pathogenic

0.79

MetaRNN

Pathogenic

0.96

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

1.4

.;L;.

PrimateAI

Uncertain

0.64

PROVEAN

Uncertain

-3.9

D;.;D

REVEL

Pathogenic

0.98

Sift

Uncertain

0.0010

D;.;D

Sift4G

Pathogenic

0.0010

D;D;D

Polyphen

1.0, 1.0

.;D;D

Vest4

0.97

MutPred

0.78

.;Loss of stability (P = 0.0186);.;

MVP

0.98

MPC

0.67

ClinPred

0.97

GERP RS

5.4

Varity_R

0.97

gMVP

0.82

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.34

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.34

Position offset: 1

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over