VCV000003599.34 - ClinVar

NM_000016.6(ACADM):c.362C>T (p.Thr121Ile)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(12)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

This variant is part of a Haplotype

NM_000016.6(ACADM):c.[351A>C;362C>T]

Identifiers

NM_000016.6(ACADM):c.362C>T (p.Thr121Ile)

Variation ID: 3599 Accession: VCV000003599.34

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1p31.1 1: 75733603 (GRCh38) [ NCBI UCSC ] 1: 76199288 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Apr 4, 2013	Oct 8, 2024	Mar 17, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000016.6:c.362C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000007.1:p.Thr121Ile	missense
NM_001127328.2:c.374C>T
NM_001127328.3:c.374C>T	NP_001120800.1:p.Thr125Ile	missense
NM_001286042.2:c.254C>T	NP_001272971.1:p.Thr85Ile	missense
NM_001286043.2:c.461C>T	NP_001272972.1:p.Thr154Ile	missense
NM_001286044.2:c.-100+681C>T		intron variant
NC_000001.11:g.75733603C>T
NC_000001.10:g.76199288C>T
NG_007045.2:g.14246C>T
LRG_838:g.14246C>T
LRG_838t1:c.362C>T	LRG_838p1:p.Thr121Ile
	P11310:p.Thr121Ile

... more HGVS ... less HGVS

Protein change

T121I, T125I, T154I, T85I

Other names

T96I
p.T121I:ACT>ATT

Canonical SPDI

NC_000001.11:75733602:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Trans-Omics for Precision Medicine (TOPMed) 0.00000

Exome Aggregation Consortium (ExAC) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00001

Links

ClinGen: CA252838 UniProtKB: P11310#VAR_015956 OMIM: 607008.0014 dbSNP: rs121434283 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
ACADM		-	-	GRCh38 GRCh37	892	924

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Medium-chain acyl-coenzyme A dehydrogenase deficiency	Pathogenic/Likely pathogenic (10)	criteria provided, multiple submitters, no conflicts	Mar 17, 2024	RCV000003782.35
not provided	Pathogenic (1)	criteria provided, single submitter	Jun 22, 2021	RCV000185674.11
ACADM-related disorder	Pathogenic (1)	no assertion criteria provided	Sep 16, 2024	RCV003924799.2

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Apr 16, 2021)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Medium-chain acyl-coenzyme A dehydrogenase deficiency Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV001623094.1 First in ClinVar: May 23, 2021 Last updated: May 23, 2021	Publications: PubMed (5) PubMed: 11349232‚ 17273963‚ 20567907‚ 18241067‚ 33123633 Comment: Variant summary: ACADM c.362C>T (p.Thr121Ile) results in a non-conservative amino acid change located in the Acyl-CoA dehydrogenase/oxidase, N-terminal domain (IPR013786) of the encoded protein sequence. … (more) Variant summary: ACADM c.362C>T (p.Thr121Ile) results in a non-conservative amino acid change located in the Acyl-CoA dehydrogenase/oxidase, N-terminal domain (IPR013786) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. However, at least one publication reports experimental evidence that this variant affects mRNA splicing and displays a high level of exon 5 skipping which leads to a premature termination codon in exon 6 (Nielsen_2007). The variant allele was found at a frequency of 1.2e-05 in 251932 control chromosomes (gnomAD and publication data). c.362C>T has been reported in the literature in the compound heterozygous and homozygous state in multiple individuals affected with Medium Chain Acyl-CoA Dehydrogenase Deficiency (Andresen_2001, Nielseri_2007, Nichols_2008, Al-Hassnan_2010, Tangeraas_2020). These data indicate that the variant is very likely to be associated with disease. At least one functional study reports this variant effect results in reducing ACADM enzymatic activity (Andresen_2001). Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=1) and pathogenic (n=4). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Pathogenic (Jun 22, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000238594.8 First in ClinVar: Jul 18, 2015 Last updated: Apr 17, 2019	Comment: Functional studies demonstrated the variant resulted in skipping of exon 5 and premature termination and decreased medium chain acyl-CoA dehydrogenase activity compared to wild type … (more) Functional studies demonstrated the variant resulted in skipping of exon 5 and premature termination and decreased medium chain acyl-CoA dehydrogenase activity compared to wild type (Nielsen et al., 2007); This variant is associated with the following publications: (PMID: 27535533, 31130284, 29268767, 24966162, 20567907, 17273963, 25503862, 11349232, 25525159) (less)
Pathogenic (Apr 05, 2018)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process) Method: clinical testing	Medium-chain acyl-coenzyme A dehydrogenase deficiency Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV000884948.2 First in ClinVar: Dec 06, 2016 Last updated: Jun 10, 2023	Comment: The ACADM c.362C>T; p.Thr121Ile variant (rs121434283), also known as T96I, has been described in the homozygous and compound heterozygous state in individuals affected with medium-chain … (more) The ACADM c.362C>T; p.Thr121Ile variant (rs121434283), also known as T96I, has been described in the homozygous and compound heterozygous state in individuals affected with medium-chain acyl-coenzyme A dehydrogenase(MCAD) deficiency (Al-Hassnan 2010, Andresen 2001, Liang 2015, Nielsen 2007). It is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 3599) and is observed in the general population at a low overall frequency of 0.001% (3/246224 alleles) in the Genome Aggregation Database. Functional analyses of this variant demonstrate reduced enzymatic activity and skipping of exon 5 (Andresen 2001, Nielsen 2007). Based on available information, this variant is considered pathogenic. References: Al-Hassnan Z et al. Medium-chain acyl-CoA dehydrogenase deficiency in Saudi Arabia: incidence, genotype, and preventive implications. J Inherit Metab Dis. 2010 Dec;33 Suppl 3:S263-7. Andresen B et al. Medium-chain acyl-CoA dehydrogenase (MCAD) mutations identified by MS/MS-based prospective screening of newborns differ from those observed in patients with clinical symptoms: identification and characterization of a new, prevalent mutation that results in mild MCAD deficiency. Am J Hum Genet. 2001 Jun;68(6):1408-18. Liang C et al. First case report of medium-chain acyl-coenzyme A dehydrogenase deficiency in China. J Pediatr Endocrinol Metab. 2015 May;28(5-6):681-4. Nielsen K et al. Seemingly neutral polymorphic variants may confer immunity to splicing-inactivating mutations: a synonymous SNP in exon 5 of MCAD protects from deleterious mutations in a flanking exonic splicing enhancer. Am J Hum Genet. 2007 Mar;80(3):416-32. (less)
Pathogenic (Nov 08, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Medium-chain acyl-coenzyme A dehydrogenase deficiency Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003808360.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Likely pathogenic (Mar 17, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Medium-chain acyl-coenzyme A dehydrogenase deficiency Affected status: unknown Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Accession: SCV004804964.2 First in ClinVar: Mar 30, 2024 Last updated: Apr 06, 2024
Pathogenic (Aug 26, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Medium-chain acyl-coenzyme A dehydrogenase deficiency Affected status: unknown Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV004847519.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024	Comment: The p.Thr121Ile variant in ACADM has been reported in >20 individuals with MCAD deficiency (Nielsen 2007 PMID: 17273963, Nichols 2008 PMID: 18241067, Al-Hassnan 2010 PMID: … (more) The p.Thr121Ile variant in ACADM has been reported in >20 individuals with MCAD deficiency (Nielsen 2007 PMID: 17273963, Nichols 2008 PMID: 18241067, Al-Hassnan 2010 PMID: 20567907). It was absent from large population studies. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. A study found that the p.Thr121Ile variant causes exon 5 skipping and a premature termination codon in exon 6 as well as decreased levels of mRNA in patient cells (Nielsen 2007 PMID: 17273963). An additional study showed that this variant reduces ACADM enzymatic activity (Andresen 2001 PMID: 11349232). This variant has also been reported in ClinVar (Variation ID 3599). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive MCAD deficiency. ACMG/AMP Criteria applied: PM3_VeryStrong, PS3_M, PP3, PM2_P. (less)
Pathogenic (Dec 30, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	Medium-chain acyl-coenzyme A dehydrogenase deficiency Affected status: yes Allele origin: unknown	Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University Accession: SCV000891587.2 First in ClinVar: Oct 10, 2018 Last updated: Dec 09, 2023	Geographic origin: Middle East
Pathogenic (Jan 29, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Medium-chain acyl-coenzyme A dehydrogenase deficiency Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000630283.7 First in ClinVar: Dec 26, 2017 Last updated: Feb 14, 2024	Publications: PubMed (6) PubMed: 28492532‚ 11349232‚ 17273963‚ 20567907‚ 24966162‚ 25503862 Comment: This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 121 of the ACADM protein (p.Thr121Ile). … (more) This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 121 of the ACADM protein (p.Thr121Ile). This variant is present in population databases (rs121434283, gnomAD 0.004%). This missense change has been observed in individual(s) with MCAD deficiency (PMID: 11349232, 17273963, 20567907, 24966162, 25503862). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It is commonly reported in individuals of Saudi ancestry (PMID: 20567907). ClinVar contains an entry for this variant (Variation ID: 3599). 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: 11349232). Studies have shown that this missense change alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 17273963). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Feb 29, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Medium-chain acyl-coenzyme A dehydrogenase deficiency Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004210704.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Pathogenic (May 03, 2017)	no assertion criteria provided Method: clinical testing	Medium Chain Acyl-CoA Dehydrogenase Deficiency Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV002092821.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022
Pathogenic (Mar 01, 2007)	no assertion criteria provided Method: literature only	MCAD DEFICIENCY Affected status: not provided Allele origin: germline	OMIM Accession: SCV000023947.3 First in ClinVar: Apr 04, 2013 Last updated: Apr 15, 2024	Publications: PubMed (2) PubMed: 11349232‚ 17273963 Comment on evidence: Andresen et al. (2001) initially reported the 362C-T mutation in the ACADM gene in a baby with MCAD deficiency (201450) identified in a U.S. MS/MS … (more) Andresen et al. (2001) initially reported the 362C-T mutation in the ACADM gene in a baby with MCAD deficiency (201450) identified in a U.S. MS/MS newborn screening program and demonstrated that the encoded T96I mutant ICAD protein had a low but detectable level of enzyme activity. Thereafter the same mutation was identified in 2 additional newborns and in 3 patients with clinically manifest disease. Nielsen et al. (2007) showed that mRNA from alleles with the 362C-T mutation displayed a high level of exon 5 skipping. Exon 5 skipping led to a shifted reading frame, resulting in a premature termination codon in exon 6, indicating that the decreased amount of MCAD mRNA from the 362C-T allele is a result of nonsense-mediated decay (NMD). The authors went on to demonstrate that the MCAD 362C-T mutation disrupts an exonic splicing enhancer (ESE). They concluded that the MCAD ESE is functionally similar to the ESE of SMN1 (600354). Further studies demonstrated that the negative effect of the 362C-T mutation is antagonized by a flanking polymorphic 351A-C synonymous variation (607008.0015). In conclusion, Nielsen et al. (2007) reported a novel mechanism by which a presumed neutral polymorphic variant, 351C, in an exon can protect against disease-causing splicing mutations. This could be a common mode by which SNPs affect gene expression, but, under normal conditions, such occurrences would be underestimated because the involved ESS elements would be unmasked only when the mutation in cis inactivates the antagonizing ESE element. Nielsen et al. (2007) suggested that this mechanism may also play an important role in evolution, since substitutions that inactivate such ESS elements would neutralize the restrictions put on splicing-inactivating mutations elsewhere in the exon. (less)
Pathogenic (Sep 16, 2024)	no assertion criteria provided Method: clinical testing	ACADM-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004742376.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: The ACADM c.362C>T variant is predicted to result in the amino acid substitution p.Thr121Ile. This variant has been reported in the homozygous and compound heterozygous … (more) The ACADM c.362C>T variant is predicted to result in the amino acid substitution p.Thr121Ile. This variant has been reported in the homozygous and compound heterozygous states in multiple individuals with medium chain acyl-CoA dehydrogenase deficiency (see for example, Table 1, Andresen et al. 2001. PubMed ID: 11349232; Table 1, Liang et al. 2015. PubMed ID: 25503862; Table 1, Wen et al. 2022. PubMed ID: 35199448). This variant is reported in 0.0046% of alleles in individuals of European (Finnish) descent in gnomAD and it has been described as a founder variant in Saudi Arabia (Al-Hassnan et al. 2010. PubMed ID: 20567907). This variant is interpreted as pathogenic. (less)
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Comment:

Variant summary: ACADM c.362C>T (p.Thr121Ile) results in a non-conservative amino acid change located in the Acyl-CoA dehydrogenase/oxidase, N-terminal domain (IPR013786) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. However, at least one publication reports experimental evidence that this variant affects mRNA splicing and displays a high level of exon 5 skipping which leads to a premature termination codon in exon 6 (Nielsen_2007). The variant allele was found at a frequency of 1.2e-05 in 251932 control chromosomes (gnomAD and publication data). c.362C>T has been reported in the literature in the compound heterozygous and homozygous state in multiple individuals affected with Medium Chain Acyl-CoA Dehydrogenase Deficiency (Andresen_2001, Nielseri_2007, Nichols_2008, Al-Hassnan_2010, Tangeraas_2020). These data indicate that the variant is very likely to be associated with disease. At least one functional study reports this variant effect results in reducing ACADM enzymatic activity (Andresen_2001). Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=1) and pathogenic (n=4). Based on the evidence outlined above, the variant was classified as pathogenic.

Comment:

Functional studies demonstrated the variant resulted in skipping of exon 5 and premature termination and decreased medium chain acyl-CoA dehydrogenase activity compared to wild type (Nielsen et al., 2007); This variant is associated with the following publications: (PMID: 27535533, 31130284, 29268767, 24966162, 20567907, 17273963, 25503862, 11349232, 25525159)

Comment:

The ACADM c.362C>T; p.Thr121Ile variant (rs121434283), also known as T96I, has been described in the homozygous and compound heterozygous state in individuals affected with medium-chain acyl-coenzyme A dehydrogenase(MCAD) deficiency (Al-Hassnan 2010, Andresen 2001, Liang 2015, Nielsen 2007). It is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 3599) and is observed in the general population at a low overall frequency of 0.001% (3/246224 alleles) in the Genome Aggregation Database. Functional analyses of this variant demonstrate reduced enzymatic activity and skipping of exon 5 (Andresen 2001, Nielsen 2007). Based on available information, this variant is considered pathogenic. References: Al-Hassnan Z et al. Medium-chain acyl-CoA dehydrogenase deficiency in Saudi Arabia: incidence, genotype, and preventive implications. J Inherit Metab Dis. 2010 Dec;33 Suppl 3:S263-7. Andresen B et al. Medium-chain acyl-CoA dehydrogenase (MCAD) mutations identified by MS/MS-based prospective screening of newborns differ from those observed in patients with clinical symptoms: identification and characterization of a new, prevalent mutation that results in mild MCAD deficiency. Am J Hum Genet. 2001 Jun;68(6):1408-18. Liang C et al. First case report of medium-chain acyl-coenzyme A dehydrogenase deficiency in China. J Pediatr Endocrinol Metab. 2015 May;28(5-6):681-4. Nielsen K et al. Seemingly neutral polymorphic variants may confer immunity to splicing-inactivating mutations: a synonymous SNP in exon 5 of MCAD protects from deleterious mutations in a flanking exonic splicing enhancer. Am J Hum Genet. 2007 Mar;80(3):416-32.

Comment:

The p.Thr121Ile variant in ACADM has been reported in >20 individuals with MCAD deficiency (Nielsen 2007 PMID: 17273963, Nichols 2008 PMID: 18241067, Al-Hassnan 2010 PMID: 20567907). It was absent from large population studies. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. A study found that the p.Thr121Ile variant causes exon 5 skipping and a premature termination codon in exon 6 as well as decreased levels of mRNA in patient cells (Nielsen 2007 PMID: 17273963). An additional study showed that this variant reduces ACADM enzymatic activity (Andresen 2001 PMID: 11349232). This variant has also been reported in ClinVar (Variation ID 3599). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive MCAD deficiency. ACMG/AMP Criteria applied: PM3_VeryStrong, PS3_M, PP3, PM2_P.

Comment:

This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 121 of the ACADM protein (p.Thr121Ile). This variant is present in population databases (rs121434283, gnomAD 0.004%). This missense change has been observed in individual(s) with MCAD deficiency (PMID: 11349232, 17273963, 20567907, 24966162, 25503862). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It is commonly reported in individuals of Saudi ancestry (PMID: 20567907). ClinVar contains an entry for this variant (Variation ID: 3599). 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: 11349232). Studies have shown that this missense change alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 17273963). For these reasons, this variant has been classified as Pathogenic.

Comment:

The ACADM c.362C>T variant is predicted to result in the amino acid substitution p.Thr121Ile. This variant has been reported in the homozygous and compound heterozygous states in multiple individuals with medium chain acyl-CoA dehydrogenase deficiency (see for example, Table 1, Andresen et al. 2001. PubMed ID: 11349232; Table 1, Liang et al. 2015. PubMed ID: 25503862; Table 1, Wen et al. 2022. PubMed ID: 35199448). This variant is reported in 0.0046% of alleles in individuals of European (Finnish) descent in gnomAD and it has been described as a founder variant in Saudi Arabia (Al-Hassnan et al. 2010. PubMed ID: 20567907). This variant is interpreted as pathogenic.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Performance of Expanded Newborn Screening in Norway Supported by Post-Analytical Bioinformatics Tools and Rapid Second-Tier DNA Analyses.	Tangeraas T	International journal of neonatal screening	2020	PMID: 33123633
First case report of medium-chain acyl-coenzyme A dehydrogenase deficiency in China.	Liang C	Journal of pediatric endocrinology & metabolism : JPEM	2015	PMID: 25503862
Functional studies of 18 heterologously expressed medium-chain acyl-CoA dehydrogenase (MCAD) variants.	Koster KL	Journal of inherited metabolic disease	2014	PMID: 24966162
Medium-chain acyl-CoA dehydrogenase deficiency in Saudi Arabia: incidence, genotype, and preventive implications.	Al-Hassnan ZN	Journal of inherited metabolic disease	2010	PMID: 20567907
Novel mutations causing medium chain acyl-CoA dehydrogenase deficiency: under-representation of the common c.985 A > G mutation in the New York state population.	Nichols MJ	American journal of medical genetics. Part A	2008	PMID: 18241067
Seemingly neutral polymorphic variants may confer immunity to splicing-inactivating mutations: a synonymous SNP in exon 5 of MCAD protects from deleterious mutations in a flanking exonic splicing enhancer.	Nielsen KB	American journal of human genetics	2007	PMID: 17273963
Medium-chain acyl-CoA dehydrogenase (MCAD) mutations identified by MS/MS-based prospective screening of newborns differ from those observed in patients with clinical symptoms: identification and characterization of a new, prevalent mutation that results in mild MCAD deficiency.	Andresen BS	American journal of human genetics	2001	PMID: 11349232

Text-mined citations for rs121434283 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 13, 2024

ClinVar Genomic variation as it relates to human health

NM_000016.6(ACADM):c.362C>T (p.Thr121Ile)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs121434283 ...