chr17-7223871-T-G

Position:

• chr17-7223871-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_000018.4(ACADVL):​c.1328T>G​(p.Met443Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,792 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).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: ACADVL NM_000018.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:3
• Conservation: PhyloP100: 5.15

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.941
• PP5: Variant 17-7223871-T-G is Pathogenic according to our data. Variant chr17-7223871-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 285852.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=3, Pathogenic=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACADVL	NM_000018.4	c.1328T>G	p.Met443Arg	missense_variant	13/20	ENST00000356839.10	NP_000009.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACADVL	ENST00000356839.10	c.1328T>G	p.Met443Arg	missense_variant	13/20	1	NM_000018.4	ENSP00000349297.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461792 Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3 AN XY: 727200

Gnomad4 AFR exome AF: 0.00

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: 0.00000270

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Very long chain acyl-CoA dehydrogenase deficiency Pathogenic:2 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Mar 08, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 17, 2019	The ACADVL c.1328T>G; p.Met443Arg variant (rs886043236) is reported in the literature in an individual with VLCAD deficiency (Schiff 2013) who was also heterozygous for another variant classified as pathogenic in ClinVar (Variation ID: 203582); cultured fibroblasts from this individual showed no detectable VLCAD activity. Furthermore, functional analysis of p.Met443Arg expressed using an in vitro prokaryotic system yielded no activity, even though protein of the correct size was detected by western blot. Additionally, another variant at this codon (c.1328T>C; p.Met443Thr) has been reported in an individual with VLCAD deficiency (Li 2015). The p.Met443Arg variant is reported in ClinVar (Variation ID: 285852), but is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The methionine at codon 443 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, this variant is considered to be likely pathogenic. References: Li X et al. Very long-chain acyl-coenzyme A dehydrogenase deficiency in Chinese patients: eight case reports, including one case of prenatal diagnosis. Eur J Med Genet. 2015 Mar;58(3):134-9. Schiff M et al. Molecular and cellular pathology of very-long-chain acyl-CoA dehydrogenase deficiency. Mol Genet Metab. 2013 May;109(1):21-7. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 08, 2023	This sequence change replaces methionine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 443 of the ACADVL protein (p.Met443Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of ACADVL-related conditions (PMID: 23480858). ClinVar contains an entry for this variant (Variation ID: 285852). 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. Experimental studies have shown that this missense change affects ACADVL function (PMID: 23480858). This variant disrupts the p.Met443 amino acid residue in ACADVL. Other variant(s) that disrupt this residue have been observed in individuals with ACADVL-related conditions (PMID: 25652019), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -
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.1328T>G (NP_000009.1:p.Met443Arg) [GRCH38: NC_000017.11:g.7223871T>G] 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 -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jan 19, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	28
DANN	Benign	0.96
DEOGEN2	Pathogenic	0.93	.;D;.
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.94	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.0	.;M;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-5.7	D;.;D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0010	D;.;D
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		0.96, 0.94	.;D;P
Vest4		0.86
MutPred		0.72		.;Gain of methylation at K444 (P = 0.0193);.;
MVP		0.99
MPC		0.84
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.99
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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

Other links and lift over

dbSNP: rs886043236; hg19: chr17-7127190;