17-7221966-G-C

Position:

• chr17-7221966-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2_Supporting PM3_Supporting PP3 PM5_Supporting PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000018.4 c.637G>C (p.Ala213Pro) in ACADVL is a missense variant predicted to cause substitution of alanine by proline at amino acid 213 (p.Ala213Pro). The highest population minor allele frequency in gnomAD V2.1.1 is 0.00018 in African/African American population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). This variant has been detected in homozygous fashion in an individual affected with very long chain acyl CoA dehydrogenase (VLCAD) deficiency, who displayed markedly reduced enzyme mRNA levels and activity (< 10 % of wildtype), which is highly specific for VLCAD deficiency (PP4_Moderate, PM3 score = 0.5, PM3_Supporting, PMID:10077518). Another missense variant c.637G>A (p.Ala213Thr) in the same codon has been classified as likely pathogenic for very long chain acyl CoA dehydrogenase (VLCAD) deficiency by the ClinGen ACADVL Variant Curation Expert Panel (PM5_Supporting). The computational predictor REVEL gives a score of 0.946, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM3_Supporting, PM5_Supporting, PP4_Moderate, PM2_Supporting, PP3 (ACADVL VCEP specifications version 1; approved November 9, 2021). LINK:https://erepo.genome.network/evrepo/ui/classification/CA233431/MONDO:0008723/021

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ACADVL ENST00000356839.10 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:4 U:1
• Conservation: PhyloP100: 6.67

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 6 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACADVL	NM_000018.4	c.637G>C	p.Ala213Pro	missense_variant	8/20	ENST00000356839.10	NP_000009.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACADVL	ENST00000356839.10	c.637G>C	p.Ala213Pro	missense_variant	8/20	1	NM_000018.4	ENSP00000349297	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251298 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135860

Gnomad AFR exome AF: 0.000185

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461848 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727228

Gnomad4 AFR exome AF: 0.0000597

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Very long chain acyl-CoA dehydrogenase deficiency Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 07, 2023	- -
Pathogenic, 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.637G>C (NP_000009.1:p.Ala213Pro) [GRCH38: NC_000017.11:g.7221966G>C] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 10077518. This variant meets the following evidence codes reported in the ACMG guidelines: PS1, PS3 -
Likely pathogenic, reviewed by expert panel	curation	ClinGen ACADVL Variant Curation Expert Panel, ClinGen	Apr 15, 2024	The NM_000018.4 c.637G>C (p.Ala213Pro) in ACADVL is a missense variant predicted to cause substitution of alanine by proline at amino acid 213 (p.Ala213Pro). The highest population minor allele frequency in gnomAD V2.1.1 is 0.00018 in African/African American population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). This variant has been detected in homozygous fashion in an individual affected with very long chain acyl CoA dehydrogenase (VLCAD) deficiency, who displayed markedly reduced enzyme mRNA levels and activity (< 10 % of wildtype), which is highly specific for VLCAD deficiency (PP4_Moderate, PM3 score = 0.5, PM3_Supporting, PMID: 10077518). Another missense variant c.637G>A (p.Ala213Thr) in the same codon has been classified as likely pathogenic for very long chain acyl CoA dehydrogenase (VLCAD) deficiency by the ClinGen ACADVL Variant Curation Expert Panel (PM5_Supporting). The computational predictor REVEL gives a score of 0.946, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM3_Supporting, PM5_Supporting, PP4_Moderate, PM2_Supporting, PP3 (ACADVL VCEP specifications version 1; approved November 9, 2021). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 01, 2023	This variant disrupts the p.Ala213 amino acid residue in ACADVL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12213615, 24801231). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 166643). This variant is also known as A173P. This missense change has been observed in individual(s) with very long chain acyl-CoA dehydrogenase deficiency (PMID: 10077518; Invitae). This variant is present in population databases (rs140629318, gnomAD 0.01%). This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 213 of the ACADVL protein (p.Ala213Pro). -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jun 26, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	.;D;.;.
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.93	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.5	.;H;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-4.8	D;.;.;D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0010	D;.;.;D
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		1.0	.;D;.;D
Vest4		0.97
MVP		0.98
MPC		0.78
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.99
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs140629318; hg19: chr17-7125285;