VCV000031135.14 - ClinVar

NM_001243279.3(ACSF3):c.1567C>T (p.Arg523Ter)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(5)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001243279.3(ACSF3):c.1567C>T (p.Arg523Ter)

Variation ID: 31135 Accession: VCV000031135.14

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 16q24.3 16: 89146003 (GRCh38) [ NCBI UCSC ] 16: 89212411 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Apr 27, 2016	Jun 17, 2024	Jan 16, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001243279.3:c.1567C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001230208.1:p.Arg523Ter	nonsense
NM_001127214.4:c.1567C>T	NP_001120686.1:p.Arg523Ter	nonsense
NM_001284316.2:c.772C>T	NP_001271245.1:p.Arg258Ter	nonsense
NM_174917.5:c.1567C>T	NP_777577.2:p.Arg523Ter	nonsense
NR_045667.2:n.693C>T		non-coding transcript variant
NR_104293.2:n.1958C>T		non-coding transcript variant
NR_147928.2:n.2002C>T		non-coding transcript variant
NR_147929.2:n.1756C>T		non-coding transcript variant
NC_000016.10:g.89146003C>T
NC_000016.9:g.89212411C>T
NG_031961.1:g.57195C>T

... more HGVS ... less HGVS

Protein change

R523*, R258*

Other names

Canonical SPDI

NC_000016.10:89146002:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00001

Links

ClinGen: CA129705 OMIM: 614245.0002 dbSNP: rs387907118 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
ACSF3		-	-	GRCh38 GRCh37	881	1082

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Combined malonic and methylmalonic acidemia	Pathogenic (5)	criteria provided, multiple submitters, no conflicts	Jan 16, 2024	RCV000024131.15

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Jan 10, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Combined malonic and methylmalonic acidemia Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002796024.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Pathogenic (Jan 16, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Combined malonic and methylmalonic acidemia Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004215599.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Pathogenic (Oct 16, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Combined malonic and methylmalonic acidemia Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000946481.4 First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024	Publications: PubMed (2) PubMed: 21841779‚ 26827111 Comment: This sequence change creates a premature translational stop signal (p.Arg523) in the ACSF3 gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Arg523) 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 (rs387907118, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with combined malonic and methylmalonic aciduria (PMID: 21841779). ClinVar contains an entry for this variant (Variation ID: 31135). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Aug 14, 2011)	no assertion criteria provided Method: literature only	COMBINED MALONIC AND METHYLMALONIC ACIDURIA Affected status: not provided Allele origin: germline	OMIM Accession: SCV000045422.2 First in ClinVar: Apr 04, 2013 Last updated: Apr 27, 2016	Publications: PubMed (1) PubMed: 21841779 Comment on evidence: In a 51-year-old man with combined malonic and methylmalonic aciduria (CMAMMA; 614265), Sloan et al. (2011) identified a C-to-T transition at nucleotide 1567 in exon … (more) In a 51-year-old man with combined malonic and methylmalonic aciduria (CMAMMA; 614265), Sloan et al. (2011) identified a C-to-T transition at nucleotide 1567 in exon 10 of the ACSF3 gene, resulting in an arg-to-ter substitution at codon 523 (R523X). The patient presented with complex partial seizures and memory problems that had onset at age 43. He carried the R558W mutation (614245.0001) on the other allele. The R523X mutation occurs in motif II of the ACSF3 protein, a conserved region involved in conformational change and catalytic function. (less)
Pathogenic (Sep 02, 2021)	no assertion criteria provided Method: clinical testing	Combined malonic and methylmalonic aciduria Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV002092436.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022

Comment:

This sequence change creates a premature translational stop signal (p.Arg523*) 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 (rs387907118, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with combined malonic and methylmalonic aciduria (PMID: 21841779). ClinVar contains an entry for this variant (Variation ID: 31135). For these reasons, this variant has been classified as Pathogenic.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
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	Molecular genetics and metabolism	2016	PMID: 26827111
Exome sequencing identifies ACSF3 as a cause of combined malonic and methylmalonic aciduria.	Sloan JL	Nature genetics	2011	PMID: 21841779

Text-mined citations for rs387907118 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_001243279.3(ACSF3):c.1567C>T (p.Arg523Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs387907118 ...