17-7223687-C-T

Position:

chr17-7223687-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PM5PP5

The ENST00000356839.10(ACADVL):c.1226C>T(p.Thr409Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000514 in 1,614,120 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T409R) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000044 ( 0 hom. )

Consequence

ACADVL
ENST00000356839.10 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:5

Conservation

PhyloP100: 1.22

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:

ACADVL (HGNC:):

ACADVL links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM1

In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in ENST00000356839.10

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr17-7223687-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1397628.Status of the report is criteria_provided_single_submitter, 1 stars.

PP5

Variant 17-7223687-C-T is Pathogenic according to our data. Variant chr17-7223687-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 21013.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=3, Uncertain_significance=4}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACADVL	NM_000018.4 linkuse as main transcript	c.1226C>T	p.Thr409Met	missense_variant	12/20	ENST00000356839.10	NP_000009.1	P49748-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACADVL	ENST00000356839.10 linkuse as main transcript	c.1226C>T	p.Thr409Met	missense_variant	12/20	1	NM_000018.4	ENSP00000349297.5		P49748-1

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00105

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000517

AC:

AN:

251476

Hom.:

AF XY:

0.0000441

AC XY:

AN XY:

135914

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000381

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000652

GnomAD4 exome

AF:

0.0000438

AC:

AN:

1461872

Hom.:

Cov.:

AF XY:

0.0000454

AC XY:

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000781

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000540

Gnomad4 OTH exome

AF:

0.000397

GnomAD4 genome

AF:

0.000125

AC:

AN:

152248

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74436

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00105

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000580

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000529

ExAC

AF:

0.0000494

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Very long chain acyl-CoA dehydrogenase deficiency

Pathogenic:3Uncertain:4

Uncertain significance, 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.1226C>T (NP_000009.1:p.Thr409Met) [GRCH38: NC_000017.11:g.7223687C>T] 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: BP4 -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 25, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 409 of the ACADVL protein (p.Thr409Met). This variant is present in population databases (rs113994169, gnomAD 0.04%). This missense change has been observed, in combination with a different pathogenic ACADVL variant, in individual(s) with very long-chain acyl-CoA dehydrogenase deficiency (VLCAD) (PMID: 24503138, 31031081; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It is commonly reported in individuals of Maori and Pacific ancestry (PMID: 26743058). Homozygous individuals have been reported with abnormal newborn screening lab results but without early-onset or severe symptoms typical for classic VLCAD; however, long term follow-up data is not available to assess risk for late-onset VLCAD (PMID: 24503138). ClinVar contains an entry for this variant (Variation ID: 21013). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 15, 2023	The ACADVL c.1226C>T; p.Thr409Met variant (rs113994169) has been reported at a high frequency in unaffected individuals of Maori and Pacific ancestry (Ryder 2016). Homozygosity for this variant has been associated with elevated C14:1 acylcarnitine levels during newborn screening, but has not been associated with the development of classical very long-chain acyl CoA dehydrogenase (VLCAD) deficiency (Evans 2016, Merritt 2014, Ryder 2016). However, these studies did not evaluate the occurrence of late-onset VLCAD symptoms during adolescence or adulthood. This variant has more recently been reported to be compound heterozygous with other ACADVL variants in individuals with VLCAD deficiency (Rovelli 2019). The p.Thr409Met variant is reported in ClinVar (Variation ID: 21013). It is observed in the general population with an overall allele frequency of 0.005% (14/282856 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.333). Based on the available information, the clinical significance of this variant is uncertain at this time. References: Evans M et al. VLCAD deficiency: Follow-up and outcome of patients diagnosed through newborn screening in Victoria. Mol Genet Metab. 2016 Aug;118(4):282-7. PMID: 27246109. Merritt JL et al. Infants suspected to have very-long chain acyl-CoA dehydrogenase deficiency from newborn screening. Mol Genet Metab. 2014 Apr;111(4):484-92. PMID: 24503138. Rovelli V et al. Clinical and biochemical outcome of patients with very long-chain acyl-CoA dehydrogenase deficiency. Mol Genet Metab. 2019 May;127(1):64-73. PMID: 31031081. Ryder B et al. The natural history of elevated tetradecenoyl-L-carnitine detected by newborn screening in New Zealand: implications for very long chain acyl-CoA dehydrogenase deficiency screening and treatment. J Inherit Metab Dis. 2016 May;39(3):409-414. PMID: 26743058. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 17, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jul 17, 2023	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with VLCAD deficiency (MIM#201475). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from threonine to methionine. (I) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v3: 19 heterozygotes, 0 homozygotes,). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2: 1 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and/or uninformative conservation. (I) 0600 - Variant is located in the annotated Acyl-CoA dehydrogenase, C-terminal domain (DECIPHER). (I) 0710 - Another missense variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. p.(Thr409Arg) has been classified as a VUS by a diagnostic laboratory in ClinVar. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. It has been classified as pathogenic and VUS by diagnostic laboratories in ClinVar. Known to be enriched in Polynesian populations, compound heterozygous individuals are likely to manifest mild disease and homozygotes tend to remain asymptomatic (PMID: 26743058, 35267200, 35400565). (I) 1001 - This variant has strong functional evidence supporting abnormal protein function. Blood spots from individuals carrying this variant (both homozygous and compound heterozygous), consistently display VLCAD deficiency and elevated C14:1-carnitine levels (PMID:31031081, 26743058, 24503138). (SP) 1207 - Parental origin of the variant is unresolved. Subsequent analysis has shown that this variant is not maternally inherited; however, a sample from this individual's father has not been tested. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 29, 2022

The c.1226C>T (p.T409M) alteration is located in exon 12 (coding exon 12) of the ACADVL gene. This alteration results from a C to T substitution at nucleotide position 1226, causing the threonine (T) at amino acid position 409 to be replaced by a methionine (M). Based on data from gnomAD, the T allele has an overall frequency of 0.005% (14/282856) total alleles studied. The highest observed frequency was 0.069% (5/7226) of Other alleles. The altered amino acid is not conserved throughout evolution:_x000D_ _x000D_ The p.T409 amino acid is not conserved in available vertebrate species. This alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Uncertain

-0.080

CADD

Uncertain

DANN

Benign

0.85

DEOGEN2

Uncertain

0.70

.;D;.

Eigen

Benign

-0.30

Eigen_PC

Benign

-0.27

FATHMM_MKL

Benign

0.53

LIST_S2

Uncertain

0.88

D;D;D

M_CAP

Uncertain

0.20

MetaRNN

Uncertain

0.47

T;T;T

MetaSVM

Uncertain

0.78

MutationAssessor

Benign

0.77

.;N;.

MutationTaster

Benign

0.48

A;A;A

PrimateAI

Benign

0.34

PROVEAN

Benign

-1.8

N;.;N

REVEL

Uncertain

0.33

Sift

Benign

0.10

T;.;T

Sift4G

Benign

0.10

T;T;T

Polyphen

0.97, 0.060

.;D;B

Vest4

0.36

MVP

0.94

MPC

0.50

ClinPred

0.12

GERP RS

2.6

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.0

Varity_R

0.040

gMVP

0.70

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

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