NM_001243279.3(ACSF3):c.1300C>T (p.Arg434Ter) AND Combined malonic and methylmalonic acidemia

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Oct 23, 2023
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:: RCV000792573.5

Allele description [Variation Report for NM_001243279.3(ACSF3):c.1300C>T (p.Arg434Ter)]

NM_001243279.3(ACSF3):c.1300C>T (p.Arg434Ter)

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.1300C>T (p.Arg434Ter)

HGVS:

NC_000016.10:g.89133196C>T
NG_031961.1:g.44388C>T
NM_001127214.4:c.1300C>T
NM_001243279.3:c.1300C>TMANE SELECT
NM_001284316.2:c.505C>T
NM_174917.5:c.1300C>T
NP_001120686.1:p.Arg434Ter
NP_001230208.1:p.Arg434Ter
NP_001271245.1:p.Arg169Ter
NP_777577.2:p.Arg434Ter
NC_000016.9:g.89199604C>T
NM_174917.4:c.1300C>T
NR_104293.2:n.1638C>T
NR_147928.2:n.1735C>T
NR_147929.2:n.1489C>T

Protein change:

R169*

Links:

dbSNP: rs766764090

NCBI 1000 Genomes Browser:

rs766764090

Molecular consequence:

NR_104293.2:n.1638C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_147928.2:n.1735C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_147929.2:n.1489C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NM_001127214.4:c.1300C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001243279.3:c.1300C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001284316.2:c.505C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_174917.5:c.1300C>T - 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
SCV000931878	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 23, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 21841779, 26827111, 28492532
SCV004210566	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jun 28, 2023)	unknown	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

SCV000931878

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 23, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV004210566

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jun 28, 2023)

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 Invitae, SCV000931878.4

#	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.Arg434*) in the ACSF3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ACSF3 are known to be pathogenic (PMID: 21841779, 26827111). This variant is present in population databases (rs766764090, gnomAD 0.006%). 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: 639703). 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 Baylor Genetics, SCV004210566.1

#	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

Last Updated: Feb 20, 2024

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