17-7224711-C-T

Variant names:

• chr17-7224711-C-T
• rs1085307648
• NM_000018.4:c.1748C>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2_Supporting PM3 PP4

This summary comes from the ClinGen Evidence Repository: The NM_000018.4(ACADVL): c.1748C>T (p.Ser583Leu) variant in ACADVL is a missense variant predicted to cause substitution of serine by leucine at amino acid 583 (p.Ser583Leu). This variant has been detected in two individuals with very long chain acyl CoA dehydrogenase (VLCAD) deficiency. Of those individuals, both were homozygous for the variant; Moreover, this variant was co-detected with c.848T>C (p.Val283Ala) variant with unknown phase (PM3 point 1.5, PMIDs 32518924, 23774949) (PM3). At least two patients with this variant in homozygous state displayed clinical phonotypes, NBS abnormalities and/or increased C14:1 levels, which is highly specific for VLCAD deficiency (PP4_Supporting, PMIDs 32518924). At least one individual with this variant was identified by newborn screen, but this information is insufficient for to use toward classification (PMID:26385305).The highest population minor allele frequency in gnomAD v2.1.1 is 0.000034 in South Asian 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 0.674, which is neither above nor below the thresholds predicting a damaging or benign impact on ACADVL function. Due to limited evidence, this variant is classified as a variant of 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, PM2_Supporting, PP4_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA397725788/MONDO:0008723/021

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: ACADVL NM_000018.4 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:6 U:1
• Conservation: PhyloP100: 4.72
• Publications: 5 publications found

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)

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 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 rank	MANE	Protein	UniProt
ACADVL	NM_000018.4	c.1748C>T	p.Ser583Leu	missense_variant	Exon 18 of 20	ENST00000356839.10	NP_000009.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACADVL	ENST00000356839.10	c.1748C>T	p.Ser583Leu	missense_variant	Exon 18 of 20	1	NM_000018.4	ENSP00000349297.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000893 AC: 2 AN: 224028 AF XY: 0.00000821

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000179

GnomAD4 exome AF: 0.00000346 AC: 5 AN: 1444792 Hom.: 0 Cov.: 36 AF XY: 0.00000557 AC XY: 4 AN XY: 717598

African (AFR) AF: 0.0000303 AC: 1 AN: 33038

American (AMR) AF: 0.00 AC: 0 AN: 42274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25748

East Asian (EAS) AF: 0.00 AC: 0 AN: 38734

South Asian (SAS) AF: 0.00 AC: 0 AN: 84552

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51562

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5634

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1103660

Other (OTH) AF: 0.0000336 AC: 2 AN: 59590

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:6 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Very long chain acyl-CoA dehydrogenase deficiency Pathogenic:5 Uncertain:1

Nov 01, 2019

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NM_000018.3:c.1748C>T (NP_000009.1:p.Ser583Leu) [GRCH38: NC_000017.11:g.7224711C>T] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 15210884. This variant meets the following evidence codes reported in the ACMG guidelines: PS1, PS3 -

Jan 06, 2017

Counsyl

Significance: Likely pathogenic

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. -

Nov 15, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. 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. This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 583 of the ACADVL protein (p.Ser583Leu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with very long chain acyl-CoA dehydrogenase deficiency (PMID: 15210884, 16464760, 23774949). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as S543L. ClinVar contains an entry for this variant (Variation ID: 550315). -

Nov 03, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ACADVL c.1748C>T; p.Ser583Leu variant (rs1085307648) is reported in the literature in multiple individuals affected with very long chain acyl-coA dehydrogenase (VLCAD) deficiency, some of whom had significantly lower VLCAD enzyme activity (Bujan 2014, Campbell 2005, Miller 2015, Ohashi 2004). This variant is reported in ClinVar (Variation ID: 550315), and is only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The serine at codon 583 is highly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.674). Additionally, another variant at this codon (c.1748C>G; p.Ser583Trp) has been reported in individuals with VLCAD deficiency (Miller 2015). Based on available information, this variant is considered to be pathogenic. References: Bujan N et al. Characterization of CoQ10 biosynthesis in fibroblasts of patients with primary and secondary CoQ10 deficiency. J Inherit Metab Dis. 2014 Jan;37(1):53-62. PMID: 23774949. Campbell CD et al. Two newborns with nutritional vitamin B12 deficiency: challenges in newborn screening for vitamin B12 deficiency. Haematologica. 2005 Dec;90(12 Suppl):ECR45. PMID: 16464760. Miller MJ et al. Recurrent ACADVL molecular findings in individuals with a positive newborn screen for very long chain acyl-coA dehydrogenase (VLCAD) deficiency in the United States. Mol Genet Metab. 2015 Nov;116(3):139-45. PMID: 26385305. Ohashi Y et al. A new diagnostic test for VLCAD deficiency using immunohistochemistry. Neurology. 2004 Jun 22;62(12):2209-13. PMID: 15210884. -

Jan 19, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 15, 2022

ClinGen ACADVL Variant Curation Expert Panel, ClinGen

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000018.4(ACADVL): c.1748C>T (p.Ser583Leu) variant in ACADVL is a missense variant predicted to cause substitution of serine by leucine at amino acid 583 (p.Ser583Leu). This variant has been detected in two individuals with very long chain acyl CoA dehydrogenase (VLCAD) deficiency. Of those individuals, both were homozygous for the variant; Moreover, this variant was co-detected with c.848T>C (p.Val283Ala) variant with unknown phase (PM3 point 1.5, PMIDs 32518924, 23774949) (PM3). At least two patients with this variant in homozygous state displayed clinical phonotypes, NBS abnormalities and/or increased C14:1 levels, which is highly specific for VLCAD deficiency (PP4_Supporting, PMIDs 32518924). At least one individual with this variant was identified by newborn screen, but this information is insufficient for to use toward classification (PMID: 26385305).The highest population minor allele frequency in gnomAD v2.1.1 is 0.000034 in South Asian 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 0.674, which is neither above nor below the thresholds predicting a damaging or benign impact on ACADVL function. Due to limited evidence, this variant is classified as a variant of 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, PM2_Supporting, PP4_Supporting. -

not provided Pathogenic:1

Nov 17, 2023

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 16464760, 26385305, 20480395, 15210884, 32518924, 23774949, 9599005) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	28
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.71	.;D;.
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	0.97	D;D;D
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.89	D;D;D
MetaSVM	Uncertain	0.68	D
MutationAssessor	Pathogenic	3.2	.;M;.
PhyloP100		4.7
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-5.9	D;.;D
REVEL	Pathogenic	0.67
Sift	Uncertain	0.0010	D;.;D
Sift4G	Benign	0.19	T;T;T
Polyphen		1.0	.;D;D
Vest4		0.91
MutPred		0.47		.;Loss of catalytic residue at S583 (P = 0.0169);.;
MVP		0.96
MPC		0.72
ClinPred		0.99	D
GERP RS		5.6
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.8
Varity_R		0.93
gMVP		0.87
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1085307648; hg19: chr17-7128030;