NM_014049.5(ACAD9):c.1641_1659dup (p.Ile554fs) AND not provided

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jan 8, 2020
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV001381042.7

Allele description [Variation Report for NM_014049.5(ACAD9):c.1641_1659dup (p.Ile554fs)]

NM_014049.5(ACAD9):c.1641_1659dup (p.Ile554fs)

Genes:

ACAD9:acyl-CoA dehydrogenase family member 9 [Gene - OMIM - HGNC]
CFAP92:cilia and flagella associated protein 92 (putative) [Gene - HGNC]

Variant type:

Duplication

Cytogenetic location:

3q21.3

Genomic location:

Preferred name:

NM_014049.5(ACAD9):c.1641_1659dup (p.Ile554fs)

HGVS:

NC_000003.12:g.128910098_128910116dup
NG_017064.1:g.35609_35627dup
NM_001348520.2:c.*183_*201dup
NM_001348521.2:c.*183_*201dup
NM_001394090.1:c.*183_*201dupMANE SELECT
NM_014049.4:c.1641_1659dupGTCGCGGGCCAGCCGCTCC
NM_014049.5:c.1641_1659dupMANE SELECT
NP_054768.2:p.Ile554fs
NC_000003.11:g.128628940_128628941insGTCGCGGGCCAGCCGCTCC
NC_000003.11:g.128628941_128628959dup
NM_014049.5:c.1641_1659dup
NR_033426.2:n.1889_1907dup

Protein change:

I554fs

Links:

dbSNP: rs755346624

NCBI 1000 Genomes Browser:

rs755346624

Molecular consequence:

NM_001348520.2:c.*183_*201dup - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_001348521.2:c.*183_*201dup - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_001394090.1:c.*183_*201dup - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_014049.5:c.1641_1659dup - frameshift variant - [Sequence Ontology: SO:0001589]
NR_033426.2:n.1889_1907dup - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001579294	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 8, 2020)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 27233227, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001579294

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 8, 2020)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

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

Citations

PubMed

Evidence of a wide spectrum of cardiac involvement due to ACAD9 mutations: Report on nine patients.

Dewulf JP, Barrea C, Vincent MF, De Laet C, Van Coster R, Seneca S, Marie S, Nassogne MC.

Mol Genet Metab. 2016 Jul;118(3):185-189. doi: 10.1016/j.ymgme.2016.05.005. Epub 2016 May 13.

PubMed [citation]

PMID:: 27233227

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Invitae, SCV001579294.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This variant has not been reported in the literature in individuals with ACAD9-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This sequence change results in a premature translational stop signal in the ACAD9 gene (p.Ile554Valfs*49). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 68 amino acids of the ACAD9 protein. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the C-terminus of the ACAD9 protein. Other variant that disrupt this region (p.Leu558Profs*45) has been determined to be pathogenic (PMID: 27233227). This suggests that variants that disrupt this region of the protein are likely to be causative of disease.

#	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

Last Updated: May 1, 2024

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