rs758928307

Positions:

chr17-7223182-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5

The NM_000018.4(ACADVL):c.1127T>C(p.Phe376Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,614,002 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. F376L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

ACADVL
NM_000018.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.52

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 9 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000018.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.951

PP5

Variant 17-7223182-T-C is Pathogenic according to our data. Variant chr17-7223182-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 203581.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=1, Pathogenic=2}. Variant chr17-7223182-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACADVL	NM_000018.4 linkuse as main transcript	c.1127T>C	p.Phe376Ser	missense_variant	11/20	ENST00000356839.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACADVL	ENST00000356839.10 linkuse as main transcript	c.1127T>C	p.Phe376Ser	missense_variant	11/20	1	NM_000018.4	P1	P49748-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

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:

0.0000119

AC:

AN:

251490

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000867

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461818

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727210

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

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:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152184

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Very long chain acyl-CoA dehydrogenase deficiency

Pathogenic:3Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 08, 2022	The ACADVL c.1127T>C; p.Phe376Ser variant (rs758928307) is reported in the literature in several individuals affected with diagnosed or suspected VLCAD deficiency, each of whom carried a second missense variant (Merinero 2018, Rovelli 2019). This variant is found in the Latino population with an allele frequency of 0.01% (3/34586 alleles) in the Genome Aggregation Database. The phenylalanine at codon 376 is moderately conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.889). However, due to limited information, the clinical significance of the p.Phe376Ser variant is uncertain at this time. References: Merinero et al. Four Years' Experience in the Diagnosis of Very Long-Chain Acyl-CoA Dehydrogenase Deficiency in Infants Detected in Three Spanish Newborn Screening Centers. JIMD Rep. 2018;39:63-74. PMID: 28755359. Rovelli 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 25, 2024	- -
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.1127T>C (NP_000009.1:p.Phe376Ser) [GRCH38: NC_000017.11:g.7223182T>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: PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 04, 2024	This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 376 of the ACADVL protein (p.Phe376Ser). This variant is present in population databases (rs758928307, gnomAD 0.009%). This missense change has been observed in individual(s) with very long-chain acyl-CoA dehydrogenase deficiency (PMID: 28755359, 31031081). 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: 203581). 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, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 13, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.76

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Pathogenic

0.31

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.93

.;D;.

Eigen

Pathogenic

0.73

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Uncertain

0.84

LIST_S2

Uncertain

0.89

D;D;D

M_CAP

Pathogenic

0.61

MetaRNN

Pathogenic

0.95

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.6

.;H;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.63

PROVEAN

Pathogenic

-6.0

D;D;D

REVEL

Pathogenic

0.89

Sift

Uncertain

0.0010

D;D;D

Sift4G

Uncertain

0.0020

D;D;D

Polyphen

0.96, 1.0

.;D;D

Vest4

0.82

MutPred

0.79

.;Gain of disorder (P = 0.0206);.;

MVP

0.99

MPC

0.85

ClinPred

0.99

GERP RS

4.5

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.1

Varity_R

0.97

gMVP

0.92

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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