NM_000016.6(ACADM):c.985A>G (p.Lys329Glu) AND not provided

Germline classification:: Pathogenic (10 submissions)
Last evaluated:: Feb 1, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000077895.48

Allele description [Variation Report for NM_000016.6(ACADM):c.985A>G (p.Lys329Glu)]

NM_000016.6(ACADM):c.985A>G (p.Lys329Glu)

Gene:

ACADM:acyl-CoA dehydrogenase medium chain [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1p31.1

Genomic location:

Preferred name:

NM_000016.6(ACADM):c.985A>G (p.Lys329Glu)

Other names:

K304E; 985A>G; c.985A>G (p.K304E); p.K329E:AAA>GAA; MC K329e

HGVS:

NC_000001.11:g.75761161A>G
NG_007045.2:g.41804A>G
NM_000016.6:c.985A>GMANE SELECT
NM_000016.6:c.985A>G
NM_001127328.2:c.997A>G
NM_001127328.3:c.997A>G
NM_001286042.2:c.877A>G
NM_001286043.2:c.1084A>G
NM_001286044.2:c.418A>G
NP_000007.1:p.Lys329Glu
NP_001120800.1:p.Lys333Glu
NP_001272971.1:p.Lys293Glu
NP_001272972.1:p.Lys362Glu
NP_001272972.1:p.Lys362Glu
NP_001272973.1:p.Lys140Glu
LRG_838t1:c.985A>G
LRG_838:g.41804A>G
LRG_838p1:p.Lys329Glu
NC_000001.10:g.76226846A>G
NM_000016.4:c.985A>G
NM_000016.5:c.985A>G
NM_001127328.1:c.997A>G
NM_001286043.1:c.1084A>G

Protein change:

K140E; LYS304GLU

Links:

OMIM: 607008.0001; dbSNP: rs77931234

NCBI 1000 Genomes Browser:

rs77931234

Molecular consequence:

NM_000016.6:c.985A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001127328.3:c.997A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001286042.2:c.877A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001286043.2:c.1084A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001286044.2:c.418A>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000238584	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Oct 23, 2019)	germline	clinical testing	Citation Link,
SCV000280721	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 30, 2015)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000887498	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Pathogenic (Oct 3, 2019)	unknown	clinical testing	PubMed (12) [See all records that cite these PMIDs] 7904584, 26223887, 25087612, 26947917, 2393404, 2394825, 2251268, 1902818, 21228398, 24966162, 35281663, 26467025
SCV001245626	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (Feb 1, 2024)	germline	clinical testing	Citation Link,
SCV001553711	Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR) See additional submitters Franklin by Genoox	no assertion criteria provided	Pathogenic	unknown	clinical testing
SCV001715540	Mayo Clinic Laboratories, Mayo Clinic	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 25, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001740388	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen - VKGL Data-share Consensus	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV001956540	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV001968564	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV002011117	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 3, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	23	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency: the prevalent mutation G985 (K304E) is subject to a strong founder effect from northwestern Europe.

Gregersen N, Winter V, Curtis D, Deufel T, Mack M, Hendrickx J, Willems PJ, Ponzone A, Parrella T, Ponzone R, et al.

Hum Hered. 1993 Nov-Dec;43(6):342-50.

PubMed [citation]

PMID:: 7904584

Medium-chain acyl-CoA dehydrogenase deficiency associated with a novel splice mutation in the ACADM gene missed by newborn screening.

Grünert SC, Wehrle A, Villavicencio-Lorini P, Lausch E, Vetter B, Schwab KO, Tucci S, Spiekerkoetter U.

BMC Med Genet. 2015 Jul 30;16:56. doi: 10.1186/s12881-015-0199-5.

PubMed [citation]

PMID:: 26223887
PMCID:: PMC4557819

See all PubMed Citations (13)

Details of each submission

From GeneDx, SCV000238584.15

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

Published functional studies demonstrate that K329E is associated with decreased thermal stability (Hara et al., 2016); This variant is associated with the following publications: (PMID: 25763512, 23509891, 25333063, 19224950, 26223887, 29317722, 27976856, 18534147, 16763904, 20301597, 26947917, 24623196, 2393404, 24718418, 12142359, 8104486, 23028790, 7730333, 7652482, 24966162, 25087612, 19780764, 23574375, 22975760, 20333879, 24799540, 24082139, 21228398, 24998633, 20036593, 23842438, 26404458, 27477829, 11763681, 26798524, 26215884, 29555771, 17186412, 29350094, 7904584, 30609409, 30626930, 31028937, 31012112, 25689098, 31836396, 31447099, 31980526, 31589614, 32853555, 32901917, 33726816)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics, SCV000280721.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	0.006939	not provided	not provided

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV000887498.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (12)

Description

The ACADM c.985A>G (p.Lys329Glu) variant has been reported in the published literature in several individuals with MCAD deficiency (PMIDs: 2251268 (1990), 2393404 (1990), 2394825 (1990), 1902818 (1991), 21228398 (2011), 24966162 (2014), 26223887 (2015), 35281663 (2022)). The variant is the most common variant among Caucasian populations and reportedly accounts for approximately 90% of alleles of symptomatic patients (PMID: 26947917 (2016)). In addition, functional studies indicate this variant causes a significant reduction in ACADM enzyme activity (PMIDs: 1902818 (1991), 24966162 (2014), 26947917 (2016)). Based on the available information, this variant is classified as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From CeGaT Center for Human Genetics Tuebingen, SCV001245626.20

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	23	not provided	not provided	clinical testing	not provided

Description

ACADM: PM3:Very Strong, PP4:Moderate, PM2:Supporting, PS3:Supporting

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		23	not provided	not provided	not provided

From Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR), SCV001553711.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

The ACADM p.K329E is widely reported as the most common pathogenic variant associated with medium-chain acyl-CoA dehydrogenase deficiency (MCADD) in the Caucasian population, accounting for approximately 56-91% of disease alleles in this population (Rhead_2006_PMID 16763904; Gramer_2015_PMID:25940036). The p.K329E variant has been identified in over 168 MCADD patients including 103 in the homozygous state, 54 in the compound heterozygous state, and 11 in the heterozygous state (Matsubara 1990_PMID 2393404; Andresen 2001_PMID11349232; Maier 2005_ PMID 15832312; Sturm 2012_PMID 23028790; FernâˆšÃ‰Â¬Â°ndez-Guerra 2014_PMID 25333063). The variant was identified in dbSNP (ID: rs77931234) and in ClinVar (classified as pathogenic by 14 laboratories and as a VUS by Genomic Research Center, Shahid Beheshti University of Medical Sciences). The variant was identified in control databases in 941 of 282786 chromosomes (1 homozygous) at a frequency of 0.003328 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 800 of 129138 chromosomes (freq: 0.006195), Other in 24 of 7220 chromosomes (freq: 0.003324), African in 33 of 24948 chromosomes (freq: 0.001323), European (Finnish) in 27 of 25124 chromosomes (freq: 0.001075), Ashkenazi Jewish in 11 of 10370 chromosomes (freq: 0.001061), Latino in 37 of 35440 chromosomes (freq: 0.001044) and South Asian in 9 of 30602 chromosomes (freq: 0.000294), but was not observed in the East Asian population. Although the p.K329E variant is identified in controls, the prevalence of this variant in affected individuals is significantly increased compared with the prevalence in controls. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.K329 residue is conserved in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. However, this variant is in a domain that is critical for enzymatic activity and in vitro functional studies have demonstrated that the p.K329E variant results in protein misfolding, increased hydrophobicity and altered enzyme kinetics (Jank_2014_PMID:24718418; Maier_2009_PMID:19224950; Koster_2014_PMID:24966162). In summary, based on the above information this variant meets our laboratoryâ€šÃ„Ã´s criteria to be classified as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Mayo Clinic Laboratories, Mayo Clinic, SCV001715540.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen - VKGL Data-share Consensus, SCV001740388.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus, SCV001956540.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus, SCV001968564.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden, SCV002011117.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Apr 15, 2024

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