rs121434283

Positions:

• chr1-75733603-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_000016.6(ACADM):​c.362C>T​(p.Thr121Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,461,708 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 (★★). Synonymous variant affecting the same amino acid position (i.e. T121T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: ACADM NM_000016.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 7.54

Genes affected

ACADM (HGNC:89): (acyl-CoA dehydrogenase medium chain) This gene encodes the medium-chain specific (C4 to C12 straight chain) acyl-Coenzyme A dehydrogenase. The homotetramer enzyme catalyzes the initial step of the mitochondrial fatty acid beta-oxidation pathway. Defects in this gene cause medium-chain acyl-CoA dehydrogenase deficiency, a disease characterized by hepatic dysfunction, fasting hypoglycemia, and encephalopathy, which can result in infantile death. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_000016.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.892
• PP5: Variant 1-75733603-C-T is Pathogenic according to our data. Variant chr1-75733603-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3599.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACADM	NM_000016.6	c.362C>T	p.Thr121Ile	missense_variant	5/12	ENST00000370841.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACADM	ENST00000370841.9	c.362C>T	p.Thr121Ile	missense_variant	5/12	1	NM_000016.6	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251432 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135892

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: 0.0000327

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1461708 Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9 AN XY: 727186

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Medium-chain acyl-coenzyme A dehydrogenase deficiency Pathogenic:10

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 29, 2024	- -
Likely pathogenic, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 17, 2024	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	May 03, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 26, 2022	The p.Thr121Ile variant in ACADM has been reported in >20 individuals with MCAD deficiency (Nielsen 2007 PMID: 17273963, Nichols 2008 PMID: 18241067, Al-Hassnan 2010 PMID: 20567907). It was absent from large population studies. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. A study found that the p.Thr121Ile variant causes exon 5 skipping and a premature termination codon in exon 6 as well as decreased levels of mRNA in patient cells (Nielsen 2007 PMID: 17273963). An additional study showed that this variant reduces ACADM enzymatic activity (Andresen 2001 PMID: 11349232). This variant has also been reported in ClinVar (Variation ID 3599). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive MCAD deficiency. ACMG/AMP Criteria applied: PM3_VeryStrong, PS3_M, PP3, PM2_P. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 121 of the ACADM protein (p.Thr121Ile). This variant is present in population databases (rs121434283, gnomAD 0.004%). This missense change has been observed in individual(s) with MCAD deficiency (PMID: 11349232, 17273963, 20567907, 24966162, 25503862). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It is commonly reported in individuals of Saudi ancestry (PMID: 20567907). ClinVar contains an entry for this variant (Variation ID: 3599). 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 not expected to disrupt ACADM protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects ACADM function (PMID: 11349232). Studies have shown that this missense change alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 17273963). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 16, 2021	Variant summary: ACADM c.362C>T (p.Thr121Ile) results in a non-conservative amino acid change located in the Acyl-CoA dehydrogenase/oxidase, N-terminal domain (IPR013786) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. However, at least one publication reports experimental evidence that this variant affects mRNA splicing and displays a high level of exon 5 skipping which leads to a premature termination codon in exon 6 (Nielsen_2007). The variant allele was found at a frequency of 1.2e-05 in 251932 control chromosomes (gnomAD and publication data). c.362C>T has been reported in the literature in the compound heterozygous and homozygous state in multiple individuals affected with Medium Chain Acyl-CoA Dehydrogenase Deficiency (Andresen_2001, Nielseri_2007, Nichols_2008, Al-Hassnan_2010, Tangeraas_2020). These data indicate that the variant is very likely to be associated with disease. At least one functional study reports this variant effect results in reducing ACADM enzymatic activity (Andresen_2001). Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=1) and pathogenic (n=4). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2007	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 05, 2018	The ACADM c.362C>T; p.Thr121Ile variant (rs121434283), also known as T96I, has been described in the homozygous and compound heterozygous state in individuals affected with medium-chain acyl-coenzyme A dehydrogenase(MCAD) deficiency (Al-Hassnan 2010, Andresen 2001, Liang 2015, Nielsen 2007). It is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 3599) and is observed in the general population at a low overall frequency of 0.001% (3/246224 alleles) in the Genome Aggregation Database. Functional analyses of this variant demonstrate reduced enzymatic activity and skipping of exon 5 (Andresen 2001, Nielsen 2007). Based on available information, this variant is considered pathogenic. References: Al-Hassnan Z et al. Medium-chain acyl-CoA dehydrogenase deficiency in Saudi Arabia: incidence, genotype, and preventive implications. J Inherit Metab Dis. 2010 Dec;33 Suppl 3:S263-7. Andresen B et al. Medium-chain acyl-CoA dehydrogenase (MCAD) mutations identified by MS/MS-based prospective screening of newborns differ from those observed in patients with clinical symptoms: identification and characterization of a new, prevalent mutation that results in mild MCAD deficiency. Am J Hum Genet. 2001 Jun;68(6):1408-18. Liang C et al. First case report of medium-chain acyl-coenzyme A dehydrogenase deficiency in China. J Pediatr Endocrinol Metab. 2015 May;28(5-6):681-4. Nielsen K et al. Seemingly neutral polymorphic variants may confer immunity to splicing-inactivating mutations: a synonymous SNP in exon 5 of MCAD protects from deleterious mutations in a flanking exonic splicing enhancer. Am J Hum Genet. 2007 Mar;80(3):416-32. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 08, 2023	- -
Pathogenic, criteria provided, single submitter	curation	Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University	Dec 30, 2017	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 22, 2021

Functional studies demonstrated the variant resulted in skipping of exon 5 and premature termination and decreased medium chain acyl-CoA dehydrogenase activity compared to wild type (Nielsen et al., 2007); This variant is associated with the following publications: (PMID: 27535533, 31130284, 29268767, 24966162, 20567907, 17273963, 25503862, 11349232, 25525159) -

ACADM-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 14, 2024

The ACADM c.362C>T variant is predicted to result in the amino acid substitution p.Thr121Ile. This variant has been reported in the homozygous and compound heterozygous states in multiple individuals with medium chain acyl-CoA dehydrogenase deficiency (see for example, Table 1, Andresen et al. 2001. PubMed ID: 11349232; Table 1, Liang et al. 2015. PubMed ID: 25503862; Table 1, Wen et al. 2022. PubMed ID: 35199448). This variant is reported in 0.0046% of alleles in individuals of European (Finnish) descent in gnomAD and it has been described as a founder variant in Saudi Arabia (Al-Hassnan et al. 2010. PubMed ID: 20567907). This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.51
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.77	D;D;D;.
Eigen	Uncertain	0.61
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D;D
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.89	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	A;A;A;A;A
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-4.4	D;D;D;D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.018	D;D;D;D
Sift4G	Benign	0.14	T;T;T;T
Polyphen		0.60	P;P;P;P
Vest4		0.96
MutPred		0.67		.;.;Gain of sheet (P = 0.1208);.;
MVP		0.97
MPC		0.41
ClinPred		0.96	D
GERP RS		5.7
Varity_R		0.89
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs121434283; hg19: chr1-76199288;