rs149678400

chr1-75745889-C-Achr1-75745889-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 7P and 1B. PM1 PM2 PM5 PP5 BP4

The NM_000016.6(ACADM):c.683C>A(p.Thr228Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000112 in 1,612,528 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T228I) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: ACADM NM_000016.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6 U:2
• Conservation: PhyloP100: 3.41

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_000016.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-75745889-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1518981.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.
• PP5: Variant 1-75745889-C-A is Pathogenic according to our data. Variant chr1-75745889-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 203538.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=3, Pathogenic=3}.
• BP4: Computational evidence support a benign effect (MetaRNN=0.09839246).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACADM	NM_000016.6	c.683C>A	p.Thr228Asn	missense_variant	8/12	ENST00000370841.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACADM	ENST00000370841.9	c.683C>A	p.Thr228Asn	missense_variant	8/12	1	NM_000016.6	P4

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 152066 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000721

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000294 AC: 74 AN: 251280 Hom.: 0 AF XY: 0.000265 AC XY: 36 AN XY: 135834

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00162

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000105 AC: 154 AN: 1460344 Hom.: 0 Cov.: 30 AF XY: 0.000100 AC XY: 73 AN XY: 726602

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00170

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: 0.0000594

Gnomad4 OTH exome AF: 0.000199

GnomAD4 genome AF: 0.000171 AC: 26 AN: 152184 Hom.: 0 Cov.: 33 AF XY: 0.000161 AC XY: 12 AN XY: 74402

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.000720

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.0000957 Hom.: 0

Bravo AF: 0.000212

ExAC AF: 0.000239 AC: 29

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Medium-chain acyl-coenzyme A dehydrogenase deficiency Pathogenic:5

Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 20, 2015	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Nov 20, 2020	The ACADM c.683C>A (p.Thr228Asn) variant is a missense variant which has been reported in four studies in a compound heterozygous state in six individuals with medium-chain acyl-CoA dehydrogenase (MCAD) deficiency (Hsu et al. 2008; Smith et al. 2010; Couce et al. 2013; Anderson et al. 2020). The p.Thr228Asn variant was also identified in another affected infant with a second variant, but the phase was not determined (McKinney et al. 2004). These individuals showed variable biochemical results including elevated acylglycines, serum medium chain acylcarnitines, C8-carnitine, C8/C10, and C8/C2 levels. However, some of biochemical parameters were within normal range in these individuals and it is suggested that this variant confers an attenuated effect (Smith et al. 2010; Couce et al. 2013; Anderson et al. 2020). The p.Thr228Asn variant is reported at a frequency of 0.001580 in the Latino/Admixed American population of the Genome Aggregation Database in a region of good sequence coverage. Based on collective evidence, the p.Thr228Asn variant is classified as likely pathogenic for medium-chain acyl-CoA dehydrogenase deficiency. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 23, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 01, 2024	Variant summary: ACADM c.683C>A (p.Thr228Asn) results in a non-conservative amino acid change located in the Acyl-CoA oxidase/dehydrogenase, middle domain (IPR006091) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00029 in 251280 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ACADM causing Medium Chain Acyl-CoA Dehydrogenase Deficiency (0.00029 vs 0.0054), allowing no conclusion about variant significance. c.683C>A has been reported in the literature in settings of newborn screening (NBS) in compound heterozygosity with other variants in this gene including multiple individuals with a pathogenic second variant in trans (example, McKinney_2004, Smith_2010, Couce_2013, Navarrete_2019, Anderson_2020, Alcaide_2022). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 20434380, 15171998, 23842438, 31836396, 30626930, 35629059). ClinVar contains an entry for this variant (Variation ID: 203538). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	This sequence change replaces threonine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 228 of the ACADM protein (p.Thr228Asn). This variant is present in population databases (rs149678400, gnomAD 0.2%). This missense change has been observed in individual(s) with MCAD deficiency (PMID: 23842438; Invitae; 15171998 20434380). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 203538). 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%. For these reasons, this variant has been classified as Pathogenic. -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 17, 2021	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(T203N); This variant is associated with the following publications: (PMID: 20434380, 26764160, 32778825, 23798014, 31836396, 23842438, 18450854, 15171998) -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 17, 2020	- -

ACADM-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 30, 2023

The ACADM c.683C>A variant is predicted to result in the amino acid substitution p.Thr228Asn. This variant has been reported in the compound heterozygous state in over twelve individuals with biochemical medium chain acyl CoA dehydrogenase deficiency (Table 4 in McKinney et al 2004. PubMed ID: 15171998; Table 2 in Smith EH et al 2010. PubMed ID: 20434380; Couce ML et al 2013. PubMed ID: 23842438; Navarrete R et al 2019. PubMed ID: 30626930; Alcaide P. et al. 2022. PubMed ID: 35629059). In some patients this variant is predicted to mildly raise c8-carnitine levels and therefore many patients are only mildly affected or may be clinically asymptomatic (Anderson DR et al 2019. PubMed ID: 31836396; Alcaide P. et al. 2022. PubMed ID: 35629059). Lymphocytes from a patient with the c.683C>A variant in combination with a null variant exhibited 31% enzyme activity (Alcaide P. et al. 2022. PubMed ID: 35629059). This variant is reported in 0.16% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-76211574-C-A). In summary, we interpret this variant as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Uncertain	-0.020
Cadd	Benign	23
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.76	D;D;D;.
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.98	D;D;D;D
M_CAP	Pathogenic	0.46	D
MetaRNN	Benign	0.098	T;T;T;T
MetaSVM	Pathogenic	1.0	D
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-3.1	D;D;D;D
REVEL	Uncertain	0.60
Sift	Benign	0.030	D;D;D;D
Sift4G	Uncertain	0.041	D;D;D;D
Polyphen		0.35	B;B;P;P
Vest4		0.48
MVP		0.95
MPC		0.45
ClinPred		0.13	T
GERP RS		4.9
Varity_R		0.73
gMVP		0.69

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: rs149678400; hg19: chr1-76211574;