17-7223865-G-C

Variant names:

• chr17-7223865-G-C
• rs2309689
• NM_000018.4:c.1322G>C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2 PM5 PP3_Strong PP5

The NM_000018.4(ACADVL):​c.1322G>C​(p.Gly441Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,780 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. G441D) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ACADVL NM_000018.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 6.58

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-7223865-G-A is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant 17-7223865-G-C is Pathogenic according to our data. Variant chr17-7223865-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 803305.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}. Variant chr17-7223865-G-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACADVL	NM_000018.4	c.1322G>C	p.Gly441Ala	missense_variant	Exon 13 of 20	ENST00000356839.10	NP_000009.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACADVL	ENST00000356839.10	c.1322G>C	p.Gly441Ala	missense_variant	Exon 13 of 20	1	NM_000018.4	ENSP00000349297.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251362 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135864

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: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461780 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727196

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Dec 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 441 of the ACADVL protein (p.Gly441Ala). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with clinical features of ACADVL-related conditions (internal data). 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: 803305). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt ACADVL protein function with a negative predictive value of 80%. This variant disrupts the p.Gly441 amino acid residue in ACADVL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8845838, 16443431, 17999356, 24305961). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

May 28, 2019

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	28
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.94	.;D;.
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.5	.;H;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-5.4	D;.;D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.029	D;.;D
Sift4G	Uncertain	0.030	D;D;D
Polyphen		0.86, 0.76	.;P;P
Vest4		0.83
MutPred		0.97		.;Gain of catalytic residue at M437 (P = 0.0468);.;
MVP		0.99
MPC		0.46
ClinPred		0.97	D
GERP RS		5.8
Varity_R		0.92
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs2309689; hg19: chr17-7127184;