rs768975918

chr17-7221679-T-Cchr17-7221679-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP5

The NM_000018.4(ACADVL):c.619T>C(p.Ser207Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,461,470 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: ACADVL NM_000018.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:3
• Conservation: PhyloP100: 0.361

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 Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_000018.4
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-7221679-T-C is Pathogenic according to our data. Variant chr17-7221679-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 551588.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=3, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACADVL	NM_000018.4	c.619T>C	p.Ser207Pro	missense_variant	7/20	ENST00000356839.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACADVL	ENST00000356839.10	c.619T>C	p.Ser207Pro	missense_variant	7/20	1	NM_000018.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000239 AC: 6 AN: 251078 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135850

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000326

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: 0.00000411 AC: 6 AN: 1461470 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 727036

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000126

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

ExAC AF: 0.0000247 AC: 3

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:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 06, 2022	- -
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.619T>C (NP_000009.1:p.Ser207Pro) [GRCH38: NC_000017.11:g.7221679T>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: PM1, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 24, 2023	This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 207 of the ACADVL protein (p.Ser207Pro). This variant is present in population databases (rs768975918, gnomAD 0.03%). This missense change has been observed in individual(s) with very long chain acyl-CoA dehydrogenase deficiency (PMID: 26385305, 26927351; Invitae). 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: 551588). 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	Counsyl	Apr 19, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 09, 2021	The ACADVL c.619T>C; p.Ser207Pro variant (rs768975918) is reported in the literature in two individuals affected with VLCAD deficiency (Ko 2016). This variant is also reported in ClinVar (Variation ID: 551588). This variant is found in the East Asian population with an allele frequency of 0.03% (6/18390 alleles) in the Genome Aggregation Database. The serine at codon 207 is moderately conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.792). However, given the lack of clinical and functional data, the significance of the p.Ser207Pro variant is uncertain at this time. References: Ko JM et al. Rare Korean Cases of Very-long-chain Acyl-CoA Dehydrogenase Deficiency with a Novel Recurrent Mutation. Ann Clin Lab Sci. 2016 Winter;46(1):97-101. PMID: 26927351. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Uncertain	0.067	T
BayesDel_noAF	Pathogenic	0.16
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.93	D;D;T;D;D
M_CAP	Pathogenic	0.88	D
MetaRNN	Uncertain	0.74	D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-3.4	D;.;.;D;.
REVEL	Pathogenic	0.79
Sift	Uncertain	0.0020	D;.;.;D;.
Sift4G	Uncertain	0.0040	D;D;D;D;D
Polyphen		0.99, 0.92	.;D;.;P;.
Vest4		0.85
MutPred		0.54		.;Gain of methylation at K204 (P = 0.1095);Gain of methylation at K204 (P = 0.1095);.;.;
MVP		0.99
MPC		0.74
ClinPred		0.97	D
GERP RS		2.2
Varity_R		0.93
gMVP		0.84

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

Publications

LitVar

Other links and lift over

dbSNP: rs768975918; hg19: chr17-7124998;