NM_000016.6(ACADM):c.583G>A (p.Gly195Arg) AND Medium-chain acyl-coenzyme A dehydrogenase deficiency

Germline classification:: Pathogenic/Likely pathogenic (8 submissions)
Last evaluated:: Mar 16, 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:: RCV000003777.37

Allele description [Variation Report for NM_000016.6(ACADM):c.583G>A (p.Gly195Arg)]

NM_000016.6(ACADM):c.583G>A (p.Gly195Arg)

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.583G>A (p.Gly195Arg)

Other names:

G170R

HGVS:

NC_000001.11:g.75740094G>A
NG_007045.2:g.20737G>A
NM_000016.6:c.583G>AMANE SELECT
NM_001127328.3:c.595G>A
NM_001286042.2:c.475G>A
NM_001286043.2:c.682G>A
NM_001286044.2:c.16G>A
NP_000007.1:p.Gly195Arg
NP_000007.1:p.Gly195Arg
NP_000007.1:p.Gly195Arg
NP_001120800.1:p.Gly199Arg
NP_001272971.1:p.Gly159Arg
NP_001272972.1:p.Gly228Arg
NP_001272973.1:p.Gly6Arg
LRG_838t1:c.583G>A
LRG_838:g.20737G>A
LRG_838p1:p.Gly195Arg
NC_000001.10:g.76205779G>A
NM_000016.4:c.583G>A
NM_000016.5:c.583G>A
P11310:p.Gly195Arg

Nucleotide change:

583G>A

Protein change:

G159R; GLY170ARG

Links:

UniProtKB: P11310#VAR_000321; OMIM: 607008.0009; dbSNP: rs121434278

NCBI 1000 Genomes Browser:

rs121434278

Molecular consequence:

NM_000016.6:c.583G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001127328.3:c.595G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001286042.2:c.475G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001286043.2:c.682G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001286044.2:c.16G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Medium-chain acyl-coenzyme A dehydrogenase deficiency (ACADMD)
Synonyms:: CARNITINE DEFICIENCY SECONDARY TO MEDIUM-CHAIN ACYL-CoA DEHYDROGENASE DEFICIENCY; MCADD; Medium chain acyl-CoA dehydrogenase deficiency
Identifiers:: MONDO: MONDO:0008721; MedGen: C0220710; Orphanet: 42; OMIM: 201450

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structural protein VP2 [Trichodysplasia spinulosa-associated polyomavirus]
structural protein VP2 [Trichodysplasia spinulosa-associated polyomavirus]
gi|814589796|gb|AKE33240.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000023942	OMIM	no assertion criteria provided	Pathogenic (Oct 1, 1994)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000220190	Counsyl	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))	Likely pathogenic (Mar 24, 2014)	unknown	literature only	PubMed (6) [See all records that cite these PMIDs] 7929823, 22975760, 9158144, 16291504, 21083904, 18241067 Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015), Citation Link,
SCV000268477	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 20, 2015)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000630291	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 21, 2024)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 7603790, 16291504, 25940036, 7929823, 9158144, 28492532
SCV000893474	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 31, 2018)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000918378	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (May 11, 2018)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25940036, 9158144 Citation Link,
SCV002092839	Natera, Inc.	no assertion criteria provided	Pathogenic (Mar 17, 2017)	germline	clinical testing
SCV004213962	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 16, 2024)	unknown	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	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, literature only
not provided	germline	unknown	1	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	literature only

Citations

PubMed

An empirical estimate of carrier frequencies for 400+ causal Mendelian variants: results from an ethnically diverse clinical sample of 23,453 individuals.

Lazarin GA, Haque IS, Nazareth S, Iori K, Patterson AS, Jacobson JL, Marshall JR, Seltzer WK, Patrizio P, Evans EA, Srinivasan BS.

Genet Med. 2013 Mar;15(3):178-86. doi: 10.1038/gim.2012.114. Epub 2012 Sep 13.

PubMed [citation]

PMID:: 22975760
PMCID:: PMC3908551

The first three years of screening for medium chain acyl-CoA dehydrogenase deficiency (MCADD) by newborn screening ontario.

Kennedy S, Potter BK, Wilson K, Fisher L, Geraghty M, Milburn J, Chakraborty P.

BMC Pediatr. 2010 Nov 17;10:82. doi: 10.1186/1471-2431-10-82.

PubMed [citation]

PMID:: 21083904
PMCID:: PMC2996355

See all PubMed Citations (10)

PMC

Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL.

Genetics in medicine : official journal of the American College of Medical Genetics. 2015 Mar 5; 17(5): 405-424

PMC [article]

PMCID:: PMC4544753
PMID:: 25741868
DOI:: 10.1038/gim.2015.30

Details of each submission

From OMIM, SCV000023942.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

MCAD deficiency (ACADMD; 201450) typically presents in the second year of life as hypoketotic hypoglycemia associated with fasting and may progress to liver failure, coma, and death. Most cases (approximately 80%) are homozygous for the lys329-to-glu mutation in the ACADM gene (607008.0001). Brackett et al. (1994) reported 4 compound heterozygous individuals from 2 unrelated families with the lys329-to-glu mutation on 1 allele and a novel G-to-A transition at nucleotide 583 as the second mutant allele. These patients presented with MCAD deficiency in the first week of life. The expressed 583G-A mutant protein lacked enzymatic activity. The novel mutation was associated with severe MCAD deficiency causing hypoglycemia or sudden unexpected neonatal death. The mutation predicts a change from glycine, a neutral amino acid with no side chain, to arginine, a positively charged residue with a bulky side chain, at amino acid 195 (G170R) of the precursor protein (residue 170 of the mature protein). This amino acid is conserved as a small neutral amino acid (glycine or alanine) in every known acyl-CoA dehydrogenase.

#	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

From Counsyl, SCV000220190.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (6)

#	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 ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV000268477.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing (GTR000500814.1)	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	(GTR000500814.1)	1	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000630291.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 195 of the ACADM protein (p.Gly195Arg). This variant is present in population databases (rs121434278, gnomAD 0.007%). This missense change has been observed in individual(s) with medium-chain acyl-CoA dehydrogenase deficiency (PMID: 7603790, 16291504, 25940036). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Gly170Arg. ClinVar contains an entry for this variant (Variation ID: 3594). 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 with a positive predictive value of 80%. Experimental studies have shown that this missense change affects ACADM function (PMID: 7929823, 9158144). For these reasons, this variant has been classified as Pathogenic.

#	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 Fulgent Genetics, Fulgent Genetics, SCV000893474.1

#	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	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000918378.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

Variant summary: ACADM c.583G>A (p.Gly195Arg) results in a non-conservative amino acid change located in the Acyl-CoA oxidase/dehydrogenase, central domain 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 3.6e-05 in 277130 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in ACADM causing Medium Chain Acyl-CoA Dehydrogenase Deficiency (3.6e-05 vs 0.0054), allowing no conclusion about variant significance. The variant, c.583G>A, has been reported in the literature in multiple individuals affected with Medium Chain Acyl-CoA Dehydrogenase Deficiency (Andresen_1997, Gramer_2015). These data indicate that the variant is very likely to be associated with disease. A functional study, Andresen_1997, showed the variant eliminated enzyme activity. Multiple ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic.

#	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 Natera, Inc., SCV002092839.1

#	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	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV004213962.2

#	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	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 3, 2024

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