17-7221993-G-C

Variant names:

• chr17-7221993-G-C
• rs398123091
• NM_000018.4:c.664G>C

Variant summary

Our verdict is Pathogenic. The variant received 26 ACMG points: 26P and 0B. PS1_Very_Strong PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000018.4(ACADVL):​c.664G>C​(p.Gly222Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,868 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 Likely pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G222A) 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: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 6.69
• Publications: 16 publications found

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 Gene-Disease associations (from GenCC):

• very long chain acyl-CoA dehydrogenase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, ClinGen, PanelApp Australia, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 26 ACMG points.

• PS1: Transcript NM_000018.4 (ACADVL) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_000018.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-7221994-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3021289.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995
• PP5: Variant 17-7221993-G-C is Pathogenic according to our data. Variant chr17-7221993-G-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1208304.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000018.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACADVL	NM_000018.4	MANE Select	c.664G>C	p.Gly222Arg	missense	Exon 8 of 20	NP_000009.1
	ACADVL	NM_001270447.2		c.733G>C	p.Gly245Arg	missense	Exon 9 of 21	NP_001257376.1
	ACADVL	NM_001033859.3		c.598G>C	p.Gly200Arg	missense	Exon 7 of 19	NP_001029031.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACADVL	ENST00000356839.10	TSL:1 MANE Select	c.664G>C	p.Gly222Arg	missense	Exon 8 of 20	ENSP00000349297.5
	ACADVL	ENST00000350303.9	TSL:1	c.598G>C	p.Gly200Arg	missense	Exon 7 of 19	ENSP00000344152.5
	ACADVL	ENST00000543245.6	TSL:2	c.733G>C	p.Gly245Arg	missense	Exon 9 of 21	ENSP00000438689.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251384 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461868 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727230

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Very long chain acyl-CoA dehydrogenase deficiency Pathogenic:4

Feb 11, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 09, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ACADVL c.664G>C; p.Gly222Arg variant (rs398123091) is reported in the literature in multiple individuals affected with very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) (Zhang 2014, Li 2015, Qian 2017). This variant is reported in ClinVar (Variation ID: 1208304) and is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. The glycine at codon 222 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.983). Additionally, the same amino acid change caused by another variant at this nucleotide position (c.664G>A; p.Gly222Arg) has been reported in individuals with VLCADD (Gobin-Limballe 2010, Voermans 2006) and ClinVar (Variation ID: 92289). Glycine 222 is part of a conserved GSD segment critical for cofactor binding, and p.Gly222Arg is predicted to disrupt this interaction (Gobin-Limballe 2010). Furthermore, in vitro functional analyses demonstrate reduced ACADVL protein levels (Gobin-Limballe 2010). Based on available information, the c.664G>C; p.Gly222Arg variant is considered to be pathogenic. References: Zhang RN et al. Clinical features and mutations in seven Chinese patients with very long chain acyl-CoA dehydrogenase deficiency. World J Pediatr. 2014 May;10(2):119-25. PMID: 24801231. 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. PMID: 25652019. Qian J et al. Applying targeted next generation sequencing to dried blood spot specimens from suspicious cases identified by tandem mass spectrometry-based newborn screening. J Pediatr Endocrinol Metab. 2017 Aug 28;30(9):979-988. PMID: 28771436. Gobin-Limballe S et al. Compared effects of missense mutations in Very-Long-Chain Acyl-CoA Dehydrogenase deficiency: Combined analysis by structural, functional and pharmacological approaches. Biochim Biophys Acta. 2010 May;1802(5):478-84. PMID: 20060901 Voermans NC et al. Rhabdomyolysis caused by an inherited metabolic disease: very long-chain acyl-CoA dehydrogenase deficiency. Am J Med. 2006 Feb;119(2):176-9. PMID: 16443431

Jun 09, 2021

Natera, Inc.

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Apr 01, 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 arginine, which is basic and polar, at codon 222 of the ACADVL protein (p.Gly222Arg). This variant is present in population databases (no rsID available, gnomAD 0.006%). This missense change has been observed in individual(s) with very long chain acyl-CoA dehydrogenase (VLCAD) deficiency (PMID: 24801231, 24898617, 25652019; Invitae). ClinVar contains an entry for this variant (Variation ID: 1208304). 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.

not provided Pathogenic:1

Mar 10, 2021

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 16443431, 20060901, 31794763, 24801231, 25652019, 26182500, 21378393)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.96	D
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.87	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		6.7
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-7.7	D
REVEL	Pathogenic	0.98
Sift	Uncertain	0.012	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.99		Gain of glycosylation at P219 (P = 0.1033)
MVP		1.0
MPC		0.84
ClinPred		1.0	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
gMVP		0.93
Mutation Taster		=0/100	disease causing

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

Other links and lift over

dbSNP: rs398123091; hg19: chr17-7125312;