rs121434280

Positions:

chr1-75732724-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2PP5_Very_StrongBP4

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

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:19

Conservation

PhyloP100: 5.80

Variant links:

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]

ACADM links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

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	Protein	UniProt
ACADM	NM_000016.6 linkuse as main transcript	c.199T>C	p.Tyr67His	missense_variant	3/12	ENST00000370841.9	NP_000007.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACADM	ENST00000370841.9 linkuse as main transcript	c.199T>C	p.Tyr67His	missense_variant	3/12	1	NM_000016.6	ENSP00000359878	P4	P11310-1

Frequencies

GnomAD3 genomes

AF:

0.000690

AC:

105

AN:

152246

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.000478

AC XY:

AN XY:

135884

show subpopulations

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.:

Cov.:

AF XY:

0.000803

AC XY:

584

AN XY:

727096

show subpopulations

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.:

Cov.:

AF XY:

0.000645

AC XY:

AN XY:

74382

show subpopulations

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.:

Bravo

AF:

0.000706

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.000610

AC:

EpiCase

AF:

0.000872

EpiControl

AF:

0.000889

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:19

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Medium-chain acyl-coenzyme A dehydrogenase deficiency

Pathogenic:14

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	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, no assertion criteria provided	literature only	OMIM	Mar 01, 2008	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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	Baylor Genetics	Mar 29, 2024	- -
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. -
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	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	clinical testing	Revvity Omics, Revvity	Jun 26, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 27, 2022	- -
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	MGZ Medical Genetics Center	Dec 08, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	May 03, 2017	- -
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 -

not provided

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 10, 2016	- -
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	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	ACADM: PM3:Very Strong, PM2, PP4:Moderate, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 25, 2021	- -

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

BayesDel_noAF

Uncertain

0.030

CADD

Benign

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

LIST_S2

Uncertain

0.92

D;D;D;D

M_CAP

Pathogenic

0.32

MetaRNN

Benign

0.020

T;T;T;T

MetaSVM

Pathogenic

0.88

MutationAssessor

Benign

0.49

.;N;.;.

MutationTaster

Benign

1.0

A;A;A;A;A

PrimateAI

Uncertain

0.68

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over