NM_012213.3(MLYCD):c.8G>A (p.Gly3Asp) AND Deficiency of malonyl-CoA decarboxylase

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Jun 20, 2022
Review status:: criteria provided, conflicting classifications

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:: RCV000004274.11

Allele description [Variation Report for NM_012213.3(MLYCD):c.8G>A (p.Gly3Asp)]

NM_012213.3(MLYCD):c.8G>A (p.Gly3Asp)

Genes:

LOC130059554:ATAC-STARR-seq lymphoblastoid silent region 7769 [Gene]
MLYCD:malonyl-CoA decarboxylase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

16q23.3

Genomic location:

Preferred name:

NM_012213.3(MLYCD):c.8G>A (p.Gly3Asp)

HGVS:

NC_000016.10:g.83899152G>A
NG_009079.1:g.5028G>A
NM_012213.3:c.8G>AMANE SELECT
NP_036345.2:p.Gly3Asp
NC_000016.9:g.83932757G>A
NM_012213.2:c.8G>A

Protein change:

G3D; GLY3ASP

Links:

OMIM: 606761.0005; dbSNP: rs121908081

NCBI 1000 Genomes Browser:

rs121908081

Molecular consequence:

NM_012213.3:c.8G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Deficiency of malonyl-CoA decarboxylase
Synonyms:: Malonic aciduria; Malonic acidemia; MCD deficiency
Identifiers:: MONDO: MONDO:0009556; MedGen: C0342793; Orphanet: 943; OMIM: 248360

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000024440	OMIM	no assertion criteria provided	Pathogenic (Oct 1, 2003)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 6145813, 12955715
SCV001226121	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jun 20, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 12955715, 28492532
SCV004046037	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000024440

OMIM

no assertion criteria provided

Pathogenic
(Oct 1, 2003)

germline

literature only

PubMed (2)
[See all records that cite these PMIDs]

SCV001226121

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jun 20, 2022)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV004046037

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic

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	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
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

Malonyl coenzyme A decarboxylase deficiency.

Brown GK, Scholem RD, Bankier A, Danks DM.

J Inherit Metab Dis. 1984;7(1):21-6.

PubMed [citation]

PMID:: 6145813

MLYCD mutation analysis: evidence for protein mistargeting as a cause of MLYCD deficiency.

Wightman PJ, Santer R, Ribes A, Dougherty F, McGill N, Thorburn DR, FitzPatrick DR.

Hum Mutat. 2003 Oct;22(4):288-300.

PubMed [citation]

PMID:: 12955715

See all PubMed Citations (4)

Details of each submission

From OMIM, SCV000024440.2

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

Description

In a patient reported by Brown et al. (1984) with MLYCD deficiency (248360), Wightman et al. (2003) found a G-to-A transition at nucleotide 8 of the cDNA predicted to result in a gly3-to-asp (G3D) protein change; the mutation was present in homozygous state. The MLYCD protein was mislocalized to the plasma membrane, suggesting that a novel targeting signal may reside in a 4-amino acid conserved N-terminal motif.

#	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 Invitae, SCV001226121.4

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

Description

This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 3 of the MLYCD protein (p.Gly3Asp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with biochemical features of MLYCD-related disorders (PMID: 12955715; Invitae). 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: 4059). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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 Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego, SCV004046037.1

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

Description

This variant has been previously reported, in one individual, as a homozygous change in patients with Malonyl-CoA decarboxylase deficiency (PMID: 12955715). Functional studies confirm this variant results in decreased mRNA levels and loss of protein function (PMID: 12955715). The c.8G>A (p.Gly3Asp) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.01150% (1/8698) and thus is presumed to be rare. The c.8G>A (p.Gly3Asp) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a discordant effect on protein function. Based on the available evidence, the c.8G>A (p.Gly3Asp) variant is classified as Likely Pathogenic.

#	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

Last Updated: Feb 4, 2024

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