VCV000225696.12 - ClinVar

NM_001170535.3(ATAD3A):c.1582C>T (p.Arg528Trp)

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.

(9)

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/Likely 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_001170535.3(ATAD3A):c.1582C>T (p.Arg528Trp)

Variation ID: 225696 Accession: VCV000225696.12

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1p36.33 1: 1529299 (GRCh38) [ NCBI UCSC ] 1: 1464679 (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	Jan 7, 2017	Mar 4, 2023	May 22, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_001170535.3:c.1582C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001164006.1:p.Arg528Trp	missense
NM_001170536.3:c.1345C>T	NP_001164007.1:p.Arg449Trp	missense
NM_018188.5:c.1726C>T	NP_060658.3:p.Arg576Trp	missense
NC_000001.11:g.1529299C>T
NC_000001.10:g.1464679C>T
NG_053035.1:g.22157C>T

... more HGVS ... less HGVS

Protein change

R528W, R576W, R449W

Other names

Canonical SPDI

NC_000001.11:1529298: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.

Links

ClinGen: CA16040614 OMIM: 612316.0001 dbSNP: rs1057517686 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.
ATAD3A		-	-	GRCh38 GRCh37	290	460

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.
Harel-Yoon syndrome	Pathogenic (7)	criteria provided, multiple submitters, no conflicts	May 22, 2022	RCV000412539.10
not provided	Pathogenic/Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Feb 17, 2022	RCV000488909.5

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.
Likely pathogenic (Apr 26, 2016)	criteria provided, single submitter (Harel et al. (Am J Hum Genet 2016)) Method: research	not provided (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine Accession: SCV000267601.1 First in ClinVar: May 22, 2017 Last updated: May 22, 2017	Publications: PubMed (1) PubMed: 27640307 Comment: recurrent de novo variant identified in 5 probands Clinical Features: Developmental delay (present) , Peripheral neuropathy (present) , Optic atrophy (present) , Cardiomyopathy (present) Family history: no
Pathogenic (Feb 08, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	HAREL-YOON SYNDROME Affected status: yes Allele origin: germline	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego Accession: SCV000996108.1 First in ClinVar: Oct 20, 2019 Last updated: Oct 20, 2019	Comment: This variant has been previously reported as a de novo change in multiple unrelated individuals with developmental delay and additional features (PMID: 27640307). An analysis … (more) This variant has been previously reported as a de novo change in multiple unrelated individuals with developmental delay and additional features (PMID: 27640307). An analysis of fibroblasts derived from an affected individual with this variant and the features of Harel-Yoon syndrome showed increased mitochondrial degradation (PMID: 27640307). Similarly, a reduction in mitochondrial content and aberrant mitochondrial morphology were observed in Drosophila harboring this mutation (PMID: 27640307). This variant is absent from the ExAC and gnomAD population databases. Algorithms developed to predict the effect of missense changes on protein function suggest this variant is likely to be deleterious. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the p.Arg576Trp variant in ATAD3A is classified as pathogenic change. (less) Number of individuals with the variant: 1
Pathogenic (-)	criteria provided, single submitter (ACGS Guidelines, 2016) Method: clinical testing	Harel-Yoon syndrome Affected status: yes Allele origin: germline	Genomics England Pilot Project, Genomics England Accession: SCV001759978.1 First in ClinVar: Jul 31, 2021 Last updated: Jul 31, 2021
Pathogenic (Jan 01, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Harel-Yoon syndrome Affected status: yes Allele origin: de novo	Provincial Medical Genetics Program of British Columbia, University of British Columbia Accession: SCV002320855.1 First in ClinVar: Apr 08, 2022 Last updated: Apr 08, 2022	Sex: male
Pathogenic (May 22, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Harel-Yoon syndrome Affected status: yes Allele origin: germline	3billion Accession: SCV002521182.1 First in ClinVar: Jun 03, 2022 Last updated: Jun 03, 2022	Publications: PubMed (1) PubMed: 27640307 Comment: The variant is not observed in the gnomAD v2.1.1 dataset. Functional studies provide strong evidence of the variant having a damaging effect on the gene … (more) The variant is not observed in the gnomAD v2.1.1 dataset. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID:27640307). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.72; 3Cnet: 0.85). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000225696). The variant has been previously reported as de novo in at least two similarly affected unrelated individuals (PMID: 27640307). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: 3-Methylglutaconic aciduria (present) , Mongolian blue spot (present) , Clinodactyly (present) , Brisk reflexes (present) , Central hypotonia (present) , Limb hypertonia (present) , Astigmatism … (more) 3-Methylglutaconic aciduria (present) , Mongolian blue spot (present) , Clinodactyly (present) , Brisk reflexes (present) , Central hypotonia (present) , Limb hypertonia (present) , Astigmatism (present) , Myopia (present) , Drooling (present) , Spastic tetraparesis (present) , Dystonic disorder (present) , Microcephaly (present) , Severe failure to thrive (present) , Global developmental delay (present) , Dysphagia (present) , Poor suck (present) , Feeding difficulties (present) (less)
Pathogenic (Feb 17, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001823919.3 First in ClinVar: Sep 08, 2021 Last updated: Mar 04, 2023	Comment: Published functional studies demonstrate a damaging effect including reduction in mitochondria density and number in motor neurons and muscle, as well as an increase in … (more) Published functional studies demonstrate a damaging effect including reduction in mitochondria density and number in motor neurons and muscle, as well as an increase in mitophagic vesicles (Harel et al., 2016); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 33146414, 27640307, 28327206, 31019026) (less)
Pathogenic (May 25, 2017)	no assertion criteria provided Method: research	Harel-Yoon Syndrome Affected status: yes Allele origin: de novo	University of Washington Center for Mendelian Genomics, University of Washington Accession: SCV000993446.1 First in ClinVar: Sep 22, 2019 Last updated: Sep 22, 2019	Publications: PubMed (1) PubMed: 27640307
Pathogenic (Mar 23, 2020)	no assertion criteria provided Method: literature only	HAREL-YOON SYNDROME Affected status: not provided Allele origin: unknown	OMIM Accession: SCV000490326.1 First in ClinVar: Jan 07, 2017 Last updated: Jan 07, 2017	Publications: PubMed (1) PubMed: 27640307 Comment on evidence: In 5 unrelated children with Harel-Yoon syndrome (HAYOS; 617183), Harel et al. (2016) identified a recurrent de novo heterozygous c.1582C-T transition (c.1582C-T, NM_001170535.1) in the … (more) In 5 unrelated children with Harel-Yoon syndrome (HAYOS; 617183), Harel et al. (2016) identified a recurrent de novo heterozygous c.1582C-T transition (c.1582C-T, NM_001170535.1) in the ATAD3A gene, resulting in an arg528-to-trp (R528W) substitution at a conserved residue. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the 1000 Genomes Project, Exome Sequencing Project, or ExAC databases, or in 5,000 in-house control exomes. Sanger sequencing suggested that the mother of 1 of the patients (patient 4) had a low level of somatic mosaicism in blood; this woman had a cardiac arrhythmia diagnosed in childhood. Another patient (patient 5) had Klinefelter syndrome; he also carried a heterozygous c.964-5G-A variant in the ATAD3A gene that was inherited from his unaffected father; studies of that variant were not performed. Functional studies of the R528W variant were not performed. Fibroblasts from 1 patient showed decreased mitochondria and mitophagic vesicles. Generation of the homologous mutation (R534W) in the Drosophila 'bor' gene resulted in lethality when expressed ubiquitously, in all neurons, or in motor neurons. Muscle-specific expression of the mutation in Drosophila led to 90% lethality and was associated with decreased mitochondrial content, aberrant mitochondrial morphology, and increased autophagic vacuoles. These findings suggested that the mutation acts as a toxic gain-of-function allele and results in decreased mitochondria in neurons and muscle. (less)
Pathogenic (-)	Flagged submission flagged submission Method: research Reason: This record appears to be redundant with a more recent record from the same submitter. Notes: SCV000494159 appears to (...more) Source: NCBI	Harel-Yoon syndrome (Autosomal dominant inheritance) Affected status: yes Allele origin: de novo	Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine Accession: SCV000494159.1 First in ClinVar: Jan 07, 2017 Last updated: Jan 07, 2017	Comment: This variant has been identified as de novo in 5 individuals with delayed motor development and hypotonia. Please see PMID: 27640307 for full description.
Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more

Comment:

This variant has been previously reported as a de novo change in multiple unrelated individuals with developmental delay and additional features (PMID: 27640307). An analysis of fibroblasts derived from an affected individual with this variant and the features of Harel-Yoon syndrome showed increased mitochondrial degradation (PMID: 27640307). Similarly, a reduction in mitochondrial content and aberrant mitochondrial morphology were observed in Drosophila harboring this mutation (PMID: 27640307). This variant is absent from the ExAC and gnomAD population databases. Algorithms developed to predict the effect of missense changes on protein function suggest this variant is likely to be deleterious. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the p.Arg576Trp variant in ATAD3A is classified as pathogenic change.

Comment:

The variant is not observed in the gnomAD v2.1.1 dataset. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID:27640307). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.72; 3Cnet: 0.85). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000225696). The variant has been previously reported as de novo in at least two similarly affected unrelated individuals (PMID: 27640307). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

Comment:

Published functional studies demonstrate a damaging effect including reduction in mitochondria density and number in motor neurons and muscle, as well as an increase in mitophagic vesicles (Harel et al., 2016); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 33146414, 27640307, 28327206, 31019026)

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
Recurrent De Novo and Biallelic Variation of ATAD3A, Encoding a Mitochondrial Membrane Protein, Results in Distinct Neurological Syndromes.	Harel T	American journal of human genetics	2016	PMID: 27640307

Text-mined citations for rs1057517686 ...

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 Dec 09, 2023

ClinVar Genomic variation as it relates to human health

NM_001170535.3(ATAD3A):c.1582C>T (p.Arg528Trp)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1057517686 ...