NM_001243279.3(ACSF3):c.1608G>A (p.Trp536Ter) AND Combined malonic and methylmalonic acidemia

Germline classification:: Pathogenic/Likely pathogenic (5 submissions)
Last evaluated:: Mar 14, 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:: RCV001062791.15

Allele description [Variation Report for NM_001243279.3(ACSF3):c.1608G>A (p.Trp536Ter)]

NM_001243279.3(ACSF3):c.1608G>A (p.Trp536Ter)

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.1608G>A (p.Trp536Ter)

HGVS:

NC_000016.10:g.89146044G>A
NG_031961.1:g.57236G>A
NM_001127214.4:c.1608G>A
NM_001243279.3:c.1608G>AMANE SELECT
NM_001284316.2:c.813G>A
NM_174917.5:c.1608G>A
NP_001120686.1:p.Trp536Ter
NP_001230208.1:p.Trp536Ter
NP_001271245.1:p.Trp271Ter
NP_777577.2:p.Trp536Ter
NC_000016.9:g.89212452G>A
NM_001127214.4:c.1608G>A
NM_174917.3:c.1608G>A
NM_174917.4:c.1608G>A
NR_045667.2:n.734G>A
NR_104293.2:n.1999G>A
NR_147928.2:n.2043G>A
NR_147929.2:n.1797G>A

Protein change:

W271*

Links:

dbSNP: rs201954387

NCBI 1000 Genomes Browser:

rs201954387

Molecular consequence:

NR_045667.2:n.734G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_104293.2:n.1999G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_147928.2:n.2043G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_147929.2:n.1797G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NM_001127214.4:c.1608G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001243279.3:c.1608G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001284316.2:c.813G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_174917.5:c.1608G>A - nonsense - [Sequence Ontology: SO:0001587]

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
SCV001227614	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 21, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 21841779, 26827111, 28492532
SCV002021282	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Oct 22, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002092438	Natera, Inc.	no assertion criteria provided	Likely pathogenic (Oct 20, 2020)	germline	clinical testing
SCV002810426	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jul 22, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004213862	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 14, 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	germline	unknown	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

Citations

PubMed

Exome sequencing identifies ACSF3 as a cause of combined malonic and methylmalonic aciduria.

Sloan JL, Johnston JJ, Manoli I, Chandler RJ, Krause C, Carrillo-Carrasco N, Chandrasekaran SD, Sysol JR, O'Brien K, Hauser NS, Sapp JC, Dorward HM, Huizing M; NIH Intramural Sequencing Center Group, Barshop BA, Berry SA, James PM, Champaigne NL, de Lonlay P, Valayannopoulos V, Geschwind MD, Gavrilov DK, et al.

Nat Genet. 2011 Aug 14;43(9):883-6. doi: 10.1038/ng.908.

PubMed [citation]

PMID:: 21841779
PMCID:: PMC3163731

Added value of next generation gene panel analysis for patients with elevated methylmalonic acid and no clinical diagnosis following functional studies of vitamin B12 metabolism.

Pupavac M, Tian X, Chu J, Wang G, Feng Y, Chen S, Fenter R, Zhang VW, Wang J, Watkins D, Wong LJ, Rosenblatt DS.

Mol Genet Metab. 2016 Mar;117(3):363-8. doi: 10.1016/j.ymgme.2016.01.008. Epub 2016 Jan 23.

PubMed [citation]

PMID:: 26827111

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001227614.5

#	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 creates a premature translational stop signal (p.Trp536*) in the ACSF3 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 41 amino acid(s) of the ACSF3 protein. This variant is present in population databases (rs201954387, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with ACSF3-related conditions. ClinVar contains an entry for this variant (Variation ID: 379920). This variant disrupts a region of the ACSF3 protein in which other variant(s) (p.Arg558Trp) have been determined to be pathogenic (PMID: 21841779, 26827111). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. 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 Revvity Omics, Revvity, SCV002021282.3

#	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 Natera, Inc., SCV002092438.1

#	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, SCV002810426.1

#	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, SCV004213862.2

#	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: Sep 29, 2024

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