NM_001243279.3(ACSF3):c.1501+1G>T AND Combined malonic and methylmalonic acidemia

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Feb 17, 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:: RCV002580689.4

Allele description [Variation Report for NM_001243279.3(ACSF3):c.1501+1G>T]

NM_001243279.3(ACSF3):c.1501+1G>T

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.1501+1G>T

HGVS:

NC_000016.10:g.89145402G>T
NG_031961.1:g.56594G>T
NM_001127214.4:c.1501+1G>T
NM_001243279.3:c.1501+1G>TMANE SELECT
NM_001284316.2:c.706+1G>T
NM_174917.5:c.1501+1G>T
NC_000016.9:g.89211810G>T

Molecular consequence:

NM_001127214.4:c.1501+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001243279.3:c.1501+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001284316.2:c.706+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
NM_174917.5:c.1501+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]

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
SCV002939714	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Mar 18, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 16199547, 21841779, 26827111, 28492532
SCV004212277	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Feb 17, 2024)	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

SCV002939714

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Mar 18, 2022)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV004212277

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Feb 17, 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

Splicing in action: assessing disease causing sequence changes.

Baralle D, Baralle M.

J Med Genet. 2005 Oct;42(10):737-48. Review.

PubMed [citation]

PMID:: 16199547
PMCID:: PMC1735933

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

See all PubMed Citations (5)

Details of each submission

From Invitae, SCV002939714.2

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

Description

This variant is not present in population databases (gnomAD no frequency). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant has not been reported in the literature in individuals affected with ACSF3-related conditions. This sequence change affects a donor splice site in intron 9 of the ACSF3 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ACSF3 are known to be pathogenic (PMID: 21841779, 26827111).

#	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, SCV004212277.2

#	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: Jun 17, 2024

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