rs370523609

Variant names:

• chr1-75745788-G-A
• rs370523609
• NM_000016.6:c.600-18G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 8P and 1B. PP5_Very_Strong BP4

The NM_000016.6(ACADM):​c.600-18G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000234 in 1,544,834 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00049 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00021 (1 hom.)
• Consequence: ACADM NM_000016.6 intron
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15
• Conservation: PhyloP100: 1.24
• Publications: 4 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: Likely_pathogenic. The variant received 7 ACMG points.

• PP5: Variant 1-75745788-G-A is Pathogenic according to our data. Variant chr1-75745788-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 226084.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACADM	NM_000016.6	c.600-18G>A		intron_variant	Intron 7 of 11	ENST00000370841.9	NP_000007.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACADM	ENST00000370841.9	c.600-18G>A		intron_variant	Intron 7 of 11	1	NM_000016.6	ENSP00000359878.5

Frequencies

GnomAD3 genomes AF: 0.000486 AC: 74 AN: 152108 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00295

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.000255 AC: 64 AN: 251270 AF XY: 0.000294

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000405

Gnomad ASJ exome AF: 0.00228

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000132

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000207 AC: 288 AN: 1392608 Hom.: 1 Cov.: 23 AF XY: 0.000207 AC XY: 144 AN XY: 697316

African (AFR) AF: 0.0000312 AC: 1 AN: 32064

American (AMR) AF: 0.000896 AC: 40 AN: 44646

Ashkenazi Jewish (ASJ) AF: 0.00257 AC: 66 AN: 25660

East Asian (EAS) AF: 0.00 AC: 0 AN: 39324

South Asian (SAS) AF: 0.0000354 AC: 3 AN: 84804

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53342

Middle Eastern (MID) AF: 0.00230 AC: 13 AN: 5642

European-Non Finnish (NFE) AF: 0.000133 AC: 139 AN: 1049034

Other (OTH) AF: 0.000448 AC: 26 AN: 58092

GnomAD4 genome AF: 0.000486 AC: 74 AN: 152226 Hom.: 1 Cov.: 33 AF XY: 0.000564 AC XY: 42 AN XY: 74408

African (AFR) AF: 0.0000963 AC: 4 AN: 41544

American (AMR) AF: 0.00294 AC: 45 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00317 AC: 11 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68014

Other (OTH) AF: 0.00284 AC: 6 AN: 2110

Alfa AF: 0.000555 Hom.: 0

Bravo AF: 0.00105

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 7 of the ACADM gene. It does not directly change the encoded amino acid sequence of the ACADM protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or altered protein product. This variant is present in population databases (rs370523609, gnomAD 0.2%). This variant has been observed in individual(s) with mild medium chain acyl-coenzyme A dehydrogenase (MCAD) deficiency on biochemical testing (PMID: 20434380, 26223887, 27308838, 27477829). 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: 226084). Studies have shown that this variant results in aberrant splicing, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 26223887). For these reasons, this variant has been classified as Pathogenic.

Feb 20, 2015

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 01, 2024

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

Dec 20, 2019

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NM_000016.4(ACADM):c.600-18G>A is classified as likely pathogenic in the context of medium chain acyl-CoA dehydrogenase deficiency and is associated with a variable presentation, ranging from clinically asymptomatic to mild. Sources cited for classification include the following: PMID 31012112, 25255367, 20434380, 27477829, 26223887, 27308838 and 30626930. Classification of NM_000016.4(ACADM):c.600-18G>A is based on the following criteria: This variant 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.

May 17, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 30, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 26, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 31, 2020

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.612-18G>A (also known as c.600-18G>A, NM_000016.4) variant in ACADM has been reported in at least 8 individuals affected with mild medium-chain acyl-CoA dehydrogenase (MCAD) deficiency in the compound heterozygous state (variant in trans in at least 3 of these cases was the common c.985A > G (p.K329E); Smith 2010, Grunert 2015, Narravula 2017) . Additionally, the c.612-18G>A variant segregated with disease in 1 affected family member (Grunert 2015). This variant has also been reported in ClinVar (variation ID 226084). It has been identified in 0.2% (24/10364) of Ashkenazi Jewish chromosomes by gnomAD (http://gnomad.broadinstitute.org). In vivo and in vitro functional assays provide evidence that this variant lead to partial missplicing of the ACADM pre-mRNA and thereby affected protein function (Grunert 2015). In summary, this variant meets criteria to be classified as likely pathogenic for autosomal recessive medium-chain acyl-CoA dehydrogenase (MCAD) deficiency. ACMG/AMP Criteria applied: PM3_strong, PS3_Moderate.

Oct 18, 2019

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 14, 2023

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: Variant summary: ACADM c.600-18G>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: four predict the variant abolishes or weakens a cryptic 5' donor site, while two predict the variant creates a novel, cryptic 3' acceptor site, by introducing a novel AG upstream of the authentic 3' splice site AG. At least one publication reports experimental evidence demonstrating that this variant creates a cryptic 3' acceptor site that competes with the original 3' splice site, thus resulting in a partial splicing defect (Grunert_2015). The variant allele was found at a frequency of 0.00025 in 251270 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ACADM causing Medium Chain Acyl-CoA Dehydrogenase Deficiency (0.00025 vs 0.0054), allowing no conclusion about variant significance. The variant, c.600-18G>A has been reported in the literature in multiple compound heterozygous individuals (who also carried a second pathogenic variant), detected during newborn screening in mostly clinically asymptomatic individuals as a biochemical phenotype (e.g. Touw_2012, Grunert_2015, Jager_2019), or in some cases in individuals with a reportedly milder form of Medium Chain Acyl-CoA Dehydrogenase Deficiency (e.g. Smith_2010). Ten submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant might represent a hypomorphic allele with variable penetrance, therefore it was classified as pathogenic for a milder disease phenotype.

not provided Pathogenic:3

Oct 03, 2019

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The gain of a new splice site is predicted. Nucleotide conservation is uninformative. Occurs in multiple cases with a lone recessive pathogenic variant in the same gene. Assessment of experimental evidence suggests this variant results in abnormal protein function.

Mar 31, 2015

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 17, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies suggest this variant leads to partial mis-splicing of the ACADM pre-mRNA (Grunert et al., 2015); This variant is associated with the following publications: (PMID: 22630369, 20434380, 27308838, 27477829, 26223887, 31012112, 30626930, 34426522, 32778825)

Inborn genetic diseases Pathogenic:1

Jun 10, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.600-18G>A intronic alteration consists of a G to A substitution 18 nucleotides before coding exon 8 in the ACADM gene. This variant has been identified in apparently unaffected homozygous individuals in our laboratory (Ambry internal data). This alteration has been reported in the compound heterozygote states in individuals with medium chain acyl CoA dehydrogenase deficiency (Grünert, 2015; Navarrete, 2019; Smith, 2010; Touw, 2012). This nucleotide position is poorly conserved in available vertebrate species. RNA studies have demonstrated that this alteration results in an incomplete splice defect (Grünert, 2015). RNA studies have demonstrated that this alteration results in an incomplete splice defect (Grünert, 2015). Based on the available evidence, this alteration is classified as pathogenic.

ACADM-related disorder Pathogenic:1

Jul 26, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ACADM c.600-18G>A variant is predicted to interfere with splicing. This variant has been registered in ClinVar as Pathogenic/Likely Pathogenic (www.ncbi.nlm.nih.gov/clinvar/variation/226084/). It is predicted to create a novel splice acceptor site 16 nucleotides upstream of the nearby canonical splice acceptor site (Alamut Visual v2.11). Functional studies indicated this variant led to partial abnormal splicing (Grünert et al. 2015. PubMed ID: 26223887). This variant has also been reported to be associated with medium chain acyl-CoA dehydrogenase deficiency (MCADD) (e.g., Grünert et al. 2015. PubMed ID: 26223887; Narravula et al. 2017. PubMed ID: 27308838) although it is not clear whether this variant is associated with a clinical phenotype (Smith et al. 2010. PubMed ID: 20434380; Grünert et al. 2015. PubMed ID: 26223887; Jager et al. 2019. PubMed ID: 31012112; Navarrete et al. 2019. PubMed ID: 30626930, Table S2). Based on these observations, we classify this variant as likely pathogenic.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	9.6
DANN	Benign	0.69
PhyloP100		1.2
Mutation Taster		=14/86	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs370523609; hg19: chr1-76211473;