VCV000551228.14 - ClinVar

NM_000017.4(ACADS):c.505A>C (p.Thr169Pro)

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.

(6)

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.

Conflicting classifications of pathogenicity
Pathogenic(1); Uncertain significance(5)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000017.4(ACADS):c.505A>C (p.Thr169Pro)

Variation ID: 551228 Accession: VCV000551228.14

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 12q24.31 12: 120737869 (GRCh38) [ NCBI UCSC ] 12: 121175672 (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	Aug 5, 2018	Feb 14, 2024	Mar 10, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000017.4:c.505A>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000008.1:p.Thr169Pro	missense
NM_001302554.2:c.473-180A>C		intron variant
NC_000012.12:g.120737869A>C
NC_000012.11:g.121175672A>C
NG_007991.1:g.17102A>C

... more HGVS ... less HGVS

Protein change

T169P

Other names

Canonical SPDI

NC_000012.12:120737868:A:C

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) 0.00000

Trans-Omics for Precision Medicine (TOPMed) 0.00000

Exome Aggregation Consortium (ExAC) 0.00002

The Genome Aggregation Database (gnomAD), exomes 0.00004

1000 Genomes Project 30x 0.00031

Links

dbSNP: rs777002501 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.
ACADS		-	-	GRCh38 GRCh37	444	463

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.
Deficiency of butyryl-CoA dehydrogenase	Conflicting interpretations of pathogenicity (6)	criteria provided, conflicting classifications	Mar 10, 2023	RCV000666229.16

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.
Uncertain significance (Apr 04, 2017)	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018)) Method: clinical testing	Deficiency of butyryl-CoA dehydrogenase Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000790487.1 First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018	Publications: PubMed (3) PubMed: 22424739‚ 18676165‚ 16926354
Uncertain significance (Jan 22, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Deficiency of butyryl-CoA dehydrogenase Affected status: yes Allele origin: maternal	Baylor Genetics Accession: SCV001526916.1 First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021	Comment: This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Uncertain significance (Nov 07, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Deficiency of butyryl-CoA dehydrogenase Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV002033268.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021
Uncertain significance (Apr 12, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Deficiency of butyryl-CoA dehydrogenase (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Genetics and Molecular Pathology, SA Pathology Additional submitter: Shariant Australia, Australian Genomics Accession: SCV002761796.1 First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 2022
Uncertain significance (May 30, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Deficiency of butyryl-CoA dehydrogenase Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003822460.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Pathogenic (Mar 10, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Deficiency of butyryl-CoA dehydrogenase Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001395667.5 First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024	Publications: PubMed (3) PubMed: 16926354‚ 18676165‚ 22424739 Comment: For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, … (more) For these reasons, this variant has been classified as Pathogenic. 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 ACADS protein function. ClinVar contains an entry for this variant (Variation ID: 551228). This missense change has been observed in individuals with short chain acyl-CoA dehydrogenase (SCAD) deficiency (PMID: 16926354, 18676165, 22424739; Invitae). This variant is present in population databases (rs777002501, gnomAD 0.04%). This sequence change replaces threonine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 169 of the ACADS protein (p.Thr169Pro). (less)

Comment:

For these reasons, this variant has been classified as Pathogenic. 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 ACADS protein function. ClinVar contains an entry for this variant (Variation ID: 551228). This missense change has been observed in individuals with short chain acyl-CoA dehydrogenase (SCAD) deficiency (PMID: 16926354, 18676165, 22424739; Invitae). This variant is present in population databases (rs777002501, gnomAD 0.04%). This sequence change replaces threonine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 169 of the ACADS protein (p.Thr169Pro).

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
Biochemical, molecular, and clinical characteristics of children with short chain acyl-CoA dehydrogenase deficiency detected by newborn screening in California.	Gallant NM	Molecular genetics and metabolism	2012	PMID: 22424739
Short-chain acyl-CoA dehydrogenase (SCAD) deficiency: an examination of the medical and neurodevelopmental characteristics of 14 cases identified through newborn screening or clinical symptoms.	Waisbren SE	Molecular genetics and metabolism	2008	PMID: 18676165
Clinical, biochemical, and genetic heterogeneity in short-chain acyl-coenzyme A dehydrogenase deficiency.	van Maldegem BT	JAMA	2006	PMID: 16926354

Text-mined citations for rs777002501 ...

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_000017.4(ACADS):c.505A>C (p.Thr169Pro)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs777002501 ...