chr1-75749553-A-T

Variant names:

• chr1-75749553-A-T
• rs780504551
• NM_000016.6:c.843A>T

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000016.6(ACADM):​c.843A>T​(p.Arg281Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,536 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R281T) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: ACADM NM_000016.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 0.968
• Publications: 8 publications found

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 Gene-Disease associations (from GenCC):

• medium chain acyl-CoA dehydrogenase deficiency

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

ACMG classification

Our verdict: Pathogenic. The variant received 19 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 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 chr1-75749552-G-C is described in CliVar as Pathogenic. Clinvar id is 3596.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 95 curated pathogenic missense variants (we use a threshold of 10). The gene has 29 curated benign missense variants. Gene score misZ: 0.54287 (below the threshold of 3.09). Trascript score misZ: 0.41658 (below the threshold of 3.09). GenCC associations: The gene is linked to medium chain acyl-CoA dehydrogenase deficiency.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 1-75749553-A-T is Pathogenic according to our data. Variant chr1-75749553-A-T is described in CliVar as Pathogenic. Clinvar id is 550313.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-75749553-A-T is described in CliVar as Pathogenic. Clinvar id is 550313.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-75749553-A-T is described in CliVar as Pathogenic. Clinvar id is 550313.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-75749553-A-T is described in CliVar as Pathogenic. Clinvar id is 550313.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-75749553-A-T is described in CliVar as Pathogenic. Clinvar id is 550313.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-75749553-A-T is described in CliVar as Pathogenic. Clinvar id is 550313.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-75749553-A-T is described in CliVar as Pathogenic. Clinvar id is 550313.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-75749553-A-T is described in CliVar as Pathogenic. Clinvar id is 550313.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-75749553-A-T is described in CliVar as Pathogenic. Clinvar id is 550313.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-75749553-A-T is described in CliVar as Pathogenic. Clinvar id is 550313.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-75749553-A-T is described in CliVar as Pathogenic. Clinvar id is 550313.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-75749553-A-T is described in CliVar as Pathogenic. Clinvar id is 550313.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-75749553-A-T is described in CliVar as Pathogenic. Clinvar id is 550313.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-75749553-A-T is described in CliVar as Pathogenic. Clinvar id is 550313.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-75749553-A-T is described in CliVar as Pathogenic. Clinvar id is 550313.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-75749553-A-T is described in CliVar as Pathogenic. Clinvar id is 550313.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-75749553-A-T is described in CliVar as Pathogenic. Clinvar id is 550313.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-75749553-A-T is described in CliVar as Pathogenic. Clinvar id is 550313.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-75749553-A-T is described in CliVar as Pathogenic. Clinvar id is 550313.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-75749553-A-T is described in CliVar as Pathogenic. Clinvar id is 550313.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-75749553-A-T is described in CliVar as Pathogenic. Clinvar id is 550313.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-75749553-A-T is described in CliVar as Pathogenic. Clinvar id is 550313.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-75749553-A-T is described in CliVar as Pathogenic. Clinvar id is 550313.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-75749553-A-T is described in CliVar as Pathogenic. Clinvar id is 550313.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-75749553-A-T is described in CliVar as Pathogenic. Clinvar id is 550313.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-75749553-A-T is described in CliVar as Pathogenic. Clinvar id is 550313.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-75749553-A-T is described in CliVar as Pathogenic. Clinvar id is 550313.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-75749553-A-T is described in CliVar as Pathogenic. Clinvar id is 550313.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACADM	NM_000016.6	c.843A>T	p.Arg281Ser	missense_variant	Exon 9 of 12	ENST00000370841.9	NP_000007.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACADM	ENST00000370841.9	c.843A>T	p.Arg281Ser	missense_variant	Exon 9 of 12	1	NM_000016.6	ENSP00000359878.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251154 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: 0.00000342 AC: 5 AN: 1461536 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727060

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39672

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111736

Other (OTH) AF: 0.00 AC: 0 AN: 60368

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Medium-chain acyl-coenzyme A dehydrogenase deficiency Pathogenic:4

Jan 27, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ACADM c.843A>T (p.Arg281Ser) results in a non-conservative amino acid change located in the medium-chain specific acyl-CoA dehydrogenase domain (IPR034180) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251154 control chromosomes. c.843A>T has been reported in the literature in individuals affected with, or expected to develop, Medium Chain Acyl-CoA Dehydrogenase Deficiency (e.g., Arnold_2010, Ensenauer_2005, Hara_2016, Purevsuren_2009, Purevsuren_2012, Tajima_2016). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (e.g., Hara_2016). The most pronounced variant effect results in approximately 1% of normal activity. The following publications have been ascertained in the context of this evaluation (PMID: 20036593, 15915086, 26947917, 22796001, 19064330, 27856190). ClinVar contains an entry for this variant (Variation ID: 550313). Based on the evidence outlined above, the variant was classified as pathogenic. -

Jun 16, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects ACADM function (PMID: 26947917). 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 ACADM protein function. ClinVar contains an entry for this variant (Variation ID: 550313). This variant is also known as p.R256S. This missense change has been observed in individual(s) with medium-chain acyl-coenzyme A dehydrogenase deficiency (PMID: 15915086, 26947917, 27856190). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs780504551, gnomAD 0.01%). This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 281 of the ACADM protein (p.Arg281Ser). -

Jan 05, 2017

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

May 03, 2017

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.55
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D;D;D;.
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Pathogenic	1.0	D;D;D;D
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.3	.;H;.;.
PhyloP100		0.97
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-5.8	D;D;D;D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.98
MutPred		0.96		.;.;Loss of methylation at R314 (P = 0.0597);.;
MVP		0.97
MPC		0.79
ClinPred		0.99	D
GERP RS		2.1
Varity_R		0.98
gMVP		0.97
Mutation Taster		=0/100	disease causing (ClinVar)

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: rs780504551; hg19: chr1-76215238;