NM_001243279.3(ACSF3):c.1672C>T (p.Arg558Trp) AND Combined malonic and methylmalonic acidemia

Germline classification:: Pathogenic/Likely pathogenic (10 submissions)
Last evaluated:: Mar 30, 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:: RCV000024130.32

Allele description [Variation Report for NM_001243279.3(ACSF3):c.1672C>T (p.Arg558Trp)]

NM_001243279.3(ACSF3):c.1672C>T (p.Arg558Trp)

Gene:

ACSF3:acyl-CoA synthetase family member 3 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

16q24.3

Genomic location:

Preferred name:

NM_001243279.3(ACSF3):c.1672C>T (p.Arg558Trp)

Other names:

p.R558W:CGG>TGG

HGVS:

NC_000016.10:g.89154148C>T
NG_031961.1:g.65340C>T
NM_001127214.4:c.1672C>T
NM_001243279.3:c.1672C>TMANE SELECT
NM_001284316.2:c.877C>T
NM_174917.5:c.1672C>T
NP_001120686.1:p.Arg558Trp
NP_001230208.1:p.Arg558Trp
NP_001271245.1:p.Arg293Trp
NP_777577.2:p.Arg558Trp
NC_000016.9:g.89220556C>T
NM_001127214.4:c.1672C>T
NM_174917.3:c.1672C>T
NM_174917.4:c.1672C>T
NR_045667.2:n.798C>T
NR_104293.2:n.2063C>T
NR_147928.2:n.2107C>T
NR_147929.2:n.1861C>T
Q4G176:p.Arg558Trp

Protein change:

R293W; ARG558TRP

Links:

UniProtKB: Q4G176#VAR_066513; OMIM: 614245.0001; dbSNP: rs141090143

NCBI 1000 Genomes Browser:

rs141090143

Molecular consequence:

NM_001127214.4:c.1672C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001243279.3:c.1672C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001284316.2:c.877C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_174917.5:c.1672C>T - missense variant - [Sequence Ontology: SO:0001583]
NR_045667.2:n.798C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_104293.2:n.2063C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_147928.2:n.2107C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_147929.2:n.1861C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Observations:

Condition(s)

Name:: Combined malonic and methylmalonic acidemia
Synonyms:: Combined malonic and methylmalonic aciduria
Identifiers:: MONDO: MONDO:0013661; MedGen: C3280314; Orphanet: 289504; OMIM: 614265

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000045421	OMIM	no assertion criteria provided	Pathogenic (Aug 14, 2011)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000711714	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely Pathogenic (Mar 25, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 21841779, 26827111, 30740739, 25741868
SCV000771502	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 31, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 21841779, 26827111, 28492532
SCV001467925	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Dec 4, 2020)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 30740739, 26827111, 21841779 Citation Link,
SCV002021283	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 24, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002061733	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 29, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002092439	Natera, Inc.	no assertion criteria provided	Pathogenic (Oct 14, 2020)	germline	clinical testing
SCV002792345	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Apr 28, 2022)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004211522	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 30, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004231900	Clinical Genomics Laboratory, Stanford Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 21, 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	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	1	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

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Combined malonic and methylmalonic aciduria due to ACSF3 mutations: Benign clinical course in an unselected cohort.

Levtova A, Waters PJ, Buhas D, Lévesque S, Auray-Blais C, Clarke JTR, Laframboise R, Maranda B, Mitchell GA, Brunel-Guitton C, Braverman NE.

J Inherit Metab Dis. 2019 Jan;42(1):107-116. doi: 10.1002/jimd.12032.

PubMed [citation]

PMID:: 30740739

See all PubMed Citations (5)

Details of each submission

From OMIM, SCV000045421.2

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

Description

In 4 individuals with combined malonic and methylmalonic aciduria (CMAMMA; 614265), Sloan et al. (2011) identified a C-to-T transition at nucleotide 1672 in exon 11 of the ACSF3 gene, resulting in an arg-to-trp substitution at codon 558 (R558W). One of the patients was homozygous; she presented at 22 months of age with seizure, encephalopathy, and recurrent ketoacidosis. The other individuals, who were compound heterozygous, presented in adulthood at ages ranging from 43 to 55 years with neurologic manifestations. The R558W mutation occurs in motif V of the ACSF3 protein, a conserved region involved in catalysis.

#	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 Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000711714.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

The p.Arg558Trp variant in ACSF3 has been reported in >10 homozygous or compound heterozygous individuals with features of combined malonic and methylmalonic acidemia, however some of those patients were asymptomatic and only had elevated methyl malonic acid levels. In several cases, this variant was found with another likely pathogenic or pathogenic variant in ACSF3, and confirmed to be in trans in at least 1 individual (Sloan 2011 PMID: 21841779, Pupavac 2016 PMID: 26827111, Levtova 2019 PMID: 30740739). At least one patient responded to cobalamin treatment (Pupavac 2016 PMID: 26827111). It was found to segregate in one sibling who had elevated methyl malonic acid levels but without clinical concerns (Levtova 2019 PMID: 30740739). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 31134). In addition, this variant has been identified in 0.58% (6822/1179774) of European chromosomes, including 18 total homozygotes by gnomAD (http://gnomad.broadinstitute.org, v.4.0.0). Although the frequency is appreciable, it is consistent with the clinical manifestation of the disease. In vitro functional studies using fibroblasts from affected homozygous and compound heterozygous individuals show increased accumulation of methylmalonic acid fibroblasts, that was restored to normal levels after transfection of a viral vector containing the ACSF3 gene, (Sloan 2011 PMID: 21841779). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive combined malonic and methylmalonic acidemia, however the impact of the biochemical phenotype on clinical features is variable. ACMG/AMP Criteria applied: PM3_VeryStrong, PP4, PP1.

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV000771502.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 558 of the ACSF3 protein (p.Arg558Trp). This variant is present in population databases (rs141090143, gnomAD 0.5%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with methylmalonic acidemia (PMID: 21841779, 26827111; 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: 31134). 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 ACSF3 protein function with a positive predictive value of 95%. 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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001467925.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

Variant summary: ACSF3 c.1672C>T (p.Arg558Trp) results in a non-conservative amino acid change located in the C-terminal domain (IPR025110) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0026 in 248458 control chromosomes (gnomAD). The variant, c.1672C>T, has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Combined Malonic and Methylmalonic Aciduria (e.g. Sloan_2011, Pupavac_2016, Levtova_2019). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified 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 Revvity Omics, Revvity, SCV002021283.3

#	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 Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center, SCV002061733.2

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

Description

PM1, PS3, PM3

#	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 Natera, Inc., SCV002092439.1

#	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 Fulgent Genetics, Fulgent Genetics, SCV002792345.1

#	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 Baylor Genetics, SCV004211522.2

#	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

From Clinical Genomics Laboratory, Stanford Medicine, SCV004231900.1

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

Description

The p.Arg558Trp variant in the ACSF3 gene has been identified in the homozygous or compound heterozygous state in many individuals diagnosed with CMAMMA (Sloan et al., 2011; Pupavac et al., 2016; Levtova et al., 2019). In several cases, this variant was confirmed to be in trans with another likely pathogenic or pathogenic variant (p.E359K, 1.7 Mb deletion spanning ACSF3), consistent with autosomal recessive inheritance. The p.Arg558Trp variant has been identified in 612/127,754 European non-Finnish chromosomes, including 1 homozygote, by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Although this variant has been seen in the general population, its frequency is low enough to be consistent with an autosomal recessive condition with reduced penetrance. Functional studies of the p.Arg558Trp variant are supportive of a deleterious effect to the protein showing significantly increased accumulation of methylmalonic acid in patient fibroblasts (Sloan et al., 2011). Computational tools also predict that this variant is deleterious; however, the accuracy of in silico algorithms is limited. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the p.Arg558Trp variant as pathogenic for autosomal recessive combined malonic and methylmalonic aciduria based on the information above. [ACMG evidence codes used: PM3_VeryStrong; PS3_Supporting; PP3]

#	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		1	not provided	not provided	not provided

Last Updated: Oct 13, 2024

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