rs121434280

chr1-75732724-T-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 12P and 1B. PM1 PM2 PP5_Very_Strong BP4

The NM_000016.6(ACADM):c.199T>C(p.Tyr67His) variant causes a missense change. The variant allele was found at a frequency of 0.000824 in 1,613,800 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00069 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00084 (0 hom.)
• Consequence: ACADM NM_000016.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:20
• Conservation: PhyloP100: 5.80

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 11 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_000016.6
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-75732724-T-C is Pathogenic according to our data. Variant chr1-75732724-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3597.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.019735634).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACADM	NM_000016.6	c.199T>C	p.Tyr67His	missense_variant	3/12	ENST00000370841.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACADM	ENST00000370841.9	c.199T>C	p.Tyr67His	missense_variant	3/12	1	NM_000016.6	P4

Frequencies

GnomAD3 genomes AF: 0.000690 AC: 105 AN: 152246 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.0374

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000911

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000501 AC: 126 AN: 251294 Hom.: 0 AF XY: 0.000478 AC XY: 65 AN XY: 135884

Gnomad AFR exome AF: 0.000309

Gnomad AMR exome AF: 0.0000578

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: 0.00103

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000838 AC: 1225 AN: 1461554 Hom.: 0 Cov.: 30 AF XY: 0.000803 AC XY: 584 AN XY: 727096

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000936

Gnomad4 NFE exome AF: 0.00108

Gnomad4 OTH exome AF: 0.000282

GnomAD4 genome AF: 0.000690 AC: 105 AN: 152246 Hom.: 0 Cov.: 33 AF XY: 0.000645 AC XY: 48 AN XY: 74382

Gnomad4 AFR AF: 0.000145

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000911

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000751 Hom.: 0

Bravo AF: 0.000706

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000610 AC: 74

EpiCase AF: 0.000872

EpiControl AF: 0.000889

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:20

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Medium-chain acyl-coenzyme A dehydrogenase deficiency Pathogenic:14

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 67 of the ACADM protein (p.Tyr67His). This variant is present in population databases (rs121434280, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of ACADM-related conditions (PMID: 16291504, 18188679, 20036593, 20434380, 22166308, 22848008, 25940036). This variant is also known as p.Y42H. ClinVar contains an entry for this variant (Variation ID: 3597). 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: 15479234, 19224950, 24718418). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 27, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Jun 15, 2022	PS3, PM2, PM3_Strong -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	-	The ACADM c.199T>C; p.Tyr67His variant (rs121434280), also known as Y42H, has been identified through newborn screening and results in an abnormal acylcarnitine profile when paired with a second ACADM pathogenic variant on the opposite allele (Maier 2009, O'Reilly 2004, Zschocke 2001). This variant is also reported as pathogenic by several laboratories in ClinVar (Variation ID: 3597). It is found in the general population with an overall allele frequency of 0.05% (140/282696 alleles) in the Genome Aggregation Database. Functional analyses demonstrate that this variant results in a temperature-sensitive enzyme with partial activity (Jank 2014, Maier 2009, O'Reilly 2004). Based on available information, this variant is considered to be pathogenic. REFERENCES Jank J et al. The domain-specific and temperature-dependent protein misfolding phenotype of variant medium-chain acyl-CoA dehydrogenase. PLoS One. 2014 Apr 9;9(4):e93852. Maier EM et al. Protein misfolding is the molecular mechanism underlying MCADD identified in newborn screening. Hum. Mol. Genet. 2009; 18(9):1612-23. O'Reilly L et al. The Y42H mutation in medium-chain acyl-CoA dehydrogenase, which is prevalent in babies identified by MS/MS-based newborn screening, is temperature sensitive. Eur. J. Biochem. 2004; 271(20):4053-63. Zschocke J et al. Molecular and functional characterisation of mild MCAD deficiency. Hum. Genet. 2001; 108(5):404-8. -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Dec 08, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 15, 2016	Variant summary: The ACADM c.199T>C (p.Tyr67His) variant located in the Acyl-CoA dehydrogenase/oxidase, N-terminal and middle domain causes a missense change involving a conserved nucleotide that 3/4 in silico tools (SNPs&GO not captured here due to low reliability) predict a benign outcome. The variant of interest was observed in controls with an allele frequency of 74/121100 (1/1636), which does not exceed the estimated maximal expected allele frequency for a pathogenic ACADM variant of 1/184. The variant of interest has been reported in multiple affected individuals as compound heterozygous, which have been implicated to have mild phenotypes, to the point where multiple authors indicate individuals with this variant do not present clinically. In addition, multiple functional studies have been performed and show the variant has a mild affect on wild type functionality. In addition, multiple clinical diagnostic laboratories/databases cite variant as "pathogenic." Therefore, taking all available information into consideration, the variant of interest has been classified as "pathogenic" for a mild MCAD phenotype. -
Pathogenic, criteria provided, single submitter	research	UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	-	The ACADM c.199T>C (p.Y67H) missense variant has been previously reported as pathogenic for medium-chain acyl-coA dehydrogenase deficiency in compound heterozygous individuals with a second, more severe ACADM variant. This variant is also referred to as Y42H (PMID: 11409868; 25940036; 11349232). -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 30, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 31, 2017	The p.Tyr71His variant in ACADM (NM_001127328.1 c.211T>C; also referred to as c. 199Y>C, T42H, and T67H) has been reported in > 15 compound heterozygous individu als with mild medium-chain acyl-CoA dehydrogenase (MCAD) deficiency (Zschocke 20 01, Touw 2013, and Gramer 2015), and segregated in 1 sibling in 1 family (Touw 2 013). This variant has also been reported in ClinVar (Variation ID#3597). This v ariant has been identified in 0.10% (69/66,614) of European chromosomes by the E xome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs12143 4280). Although this variant has been seen in the general population, its freque ncy is low enough to be consistent with a recessive carrier frequency, particula rly with one presenting with a mild phenotype. In vitro functional studies provi de some evidence that the p.Tyr71 variant may modestly impact protein function ( O'Reilly 2004, Maier 2009, Koster 2014, Jank 2014, and Hara 2016). However, thes e assays show a decreased, but not eliminated, residual activity. It is unclear how this mild biochemical reduction may lead to a clinical phenotype. In summary , although additional studies are required to fully establish its clinical signi ficance, the p.Tyr71His variant is likely pathogenic in an autosomal recessive m anner for mild MCAD deficiency. -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 02, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with medium chain acyl-CoA dehydrogenase (MCAD) deficiency (MIM#201450). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from tyrosine to histidine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 140 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2: 1 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated Acyl-CoA dehydrogenase, N-terminal domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. Also known as p.(Ty42His), it is known as a common European variant and accounts for approximately 7% of all alleles identified in individuals with a positive MCAD deficiency result on newborn screening. It is also known to be associated with a milder clinical phenotype (GeneReviews). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2008	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	May 03, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 26, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 20, 2019	NM_000016.4(ACADM):c.199T>C(Y67H) is classified as pathogenic in the context of medium chain acyl-CoA dehydrogenase deficiency and is associated with a mild form of this disease. Sources cited for classification include the following: PMIDs: 15832312, 20434380, 11409868, 19224950, 23028790, 23509891, and 24718418. Classification of NM_000016.4(ACADM):c.199T>C(Y67H) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 25, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 06, 2023	Published functional studies found this variant is associated with a mild reduction of enzyme activity at higher temperatures and partial rescue of enzyme activity with chaperonins suggesting this variant results in a mild folding defect (Andresen BS et al., 2001; Maier EM et a l., 2009; Koster KL et al., 2014); Also known as p.(Y42H); This variant is associated with the following publications: (PMID: 26947917, 15832312, 25087612, 22975760, 26223887, 24718418, 35460704, 24966162, 23509891, 30609409, 31012112, 32778825, 23028790, 25940036, 11349232, 19780764, 33580884, 19224950, 31980526, 34850845, 15479234, 11409868) -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 10, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 24, 2017	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 04, 2020

The c.199T>C (p.Y67H) alteration is located in exon 3 (coding exon 3) of the ACADM gene. This alteration results from a T to C substitution at nucleotide position 199, causing the tyrosine (Y) at amino acid position 67 to be replaced by a histidine (H). Based on data from the Genome Aggregation Database (gnomAD), the ACADM c.199T>C alteration was observed in 0.05% (140/282696) of total alleles studied, with a frequency of 0.1% (131/129102) in the European (non-Finnish) subpopulation. The p.Y67H alteration (also known as Y42H) is the second most frequent mutation identified among patients with medium chain acyl CoA dehydrogenase deficiency (MCADD) and is reported in the compound heterozygous state with the common European founder mutation c.985A>G in the majority of cases (Andresen, 2001; Maier, 2005; Gramer, 2015). Functional studies demonstrate that this is a temperature-sensitive mutation with mild effects on secondary protein structure and residual enzyme activity (Andresen, 2001; O'Reilly, 2004; Jank, 2014). The in silico prediction for the p.Y67H alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Uncertain	0.030
Cadd	Benign	23
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.63	D;D;D;.
Eigen	Benign	-0.13
Eigen_PC	Benign	0.054
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;D;D;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Benign	0.020	T;T;T;T
MetaSVM	Pathogenic	0.88	D
MutationTaster	Benign	1.0	A;A;A;A;A
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-2.4	N;N;N;N
REVEL	Uncertain	0.56
Sift	Benign	0.29	T;T;T;T
Sift4G	Benign	0.37	T;T;T;T
Polyphen		0.012	B;B;B;B
Vest4		0.56
MVP		0.99
MPC		0.26
ClinPred		0.056	T
GERP RS		4.5
Varity_R		0.47
gMVP		0.78

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: rs121434280; hg19: chr1-76198409;