VCV000488508.19 - ClinVar

NM_014297.5(ETHE1):c.586G>A (p.Asp196Asn)

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.

(7)

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_014297.5(ETHE1):c.586G>A (p.Asp196Asn)

Variation ID: 488508 Accession: VCV000488508.19

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 19q13.31 19: 43508784 (GRCh38) [ NCBI UCSC ] 19: 44012936 (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	Feb 8, 2018	Oct 26, 2024	Aug 15, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_014297.5:c.586G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_055112.2:p.Asp196Asn	missense
NM_001320867.2:c.553G>A	NP_001307796.1:p.Asp185Asn	missense
NM_001320868.2:c.217G>A	NP_001307797.1:p.Asp73Asn	missense
NM_001320869.2:c.292G>A	NP_001307798.1:p.Asp98Asn	missense
NC_000019.10:g.43508784C>T
NC_000019.9:g.44012936C>T
NG_008141.1:g.23461G>A

... more HGVS ... less HGVS

Protein change

D196N, D98N, D185N, D73N

Other names

Canonical SPDI

NC_000019.10:43508783: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.

Exome Aggregation Consortium (ExAC) 0.00002

The Genome Aggregation Database (gnomAD), exomes 0.00003

Links

ClinGen: CA9487819 OMIM: 608451.0011 dbSNP: rs763799125 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.
ETHE1		-	-	GRCh38 GRCh37	407	445

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.
Ethylmalonic encephalopathy	Pathogenic/Likely pathogenic (5)	criteria provided, multiple submitters, no conflicts	Feb 6, 2024	RCV000578436.21
not provided	Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Aug 15, 2024	RCV002307552.18

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 (Nov 16, 2017)	criteria provided, single submitter (Classification criteria August 2017) Method: clinical testing	Ethylmalonic encephalopathy (Autosomal recessive inheritance) Affected status: yes Allele origin: maternal	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München Accession: SCV000680216.1 First in ClinVar: Feb 08, 2018 Last updated: Feb 08, 2018	Sex: female Tissue: blood
Likely pathogenic (May 16, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Ethylmalonic encephalopathy Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV001366738.2 First in ClinVar: Jul 06, 2020 Last updated: Dec 12, 2020	Comment: This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PP2,PP3.
Likely pathogenic (Feb 06, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Ethylmalonic encephalopathy Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004197154.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Likely pathogenic (Aug 15, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV002601309.3 First in ClinVar: Nov 19, 2022 Last updated: Oct 13, 2024	Comment: Published functional studies suggest a damaging effect resulting from a higher affinity of the enzyme for its substrate (PMID: 23144459); Not observed at significant frequency … (more) Published functional studies suggest a damaging effect resulting from a higher affinity of the enzyme for its substrate (PMID: 23144459); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18593870, Sloan-Heggen2023[Abstract], 36891747, 23144459) (less)
Likely pathogenic (Jun 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV004702598.8 First in ClinVar: Mar 10, 2024 Last updated: Oct 20, 2024	Comment: ETHE1: PM2, PM3, PM5, PS3:Supporting Number of individuals with the variant: 3
Pathogenic (Oct 21, 2024)	no assertion criteria provided Method: literature only	ENCEPHALOPATHY, ETHYLMALONIC Affected status: not provided Allele origin: germline	OMIM Accession: SCV005375486.1 First in ClinVar: Oct 26, 2024 Last updated: Oct 26, 2024	Publications: PubMed (1) PubMed: 36891747 Comment on evidence: In a 4-year-old boy, born to consanguineous parents, with ethylmalonic encephalopathy (EE; 602473), Kashima et al. (2023) identified homozygosity for a c.586G-A transition in the … (more) In a 4-year-old boy, born to consanguineous parents, with ethylmalonic encephalopathy (EE; 602473), Kashima et al. (2023) identified homozygosity for a c.586G-A transition in the ETHE1 gene, resulting in an asp196-to-asn (D196N) substitution. The mutation was identified by whole-exome sequencing. (less)
not provided (-)	no classification provided Method: literature only	Ethylmalonic encephalopathy Affected status: unknown Allele origin: germline	GeneReviews Accession: SCV000710836.2 First in ClinVar: Apr 02, 2018 Last updated: Oct 01, 2022	Publications: PubMed (1) PubMed: 28933811 BookShelf: NBK453432 BookShelf: NBK453432

Comment:

Published functional studies suggest a damaging effect resulting from a higher affinity of the enzyme for its substrate (PMID: 23144459); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18593870, Sloan-Heggen2023[Abstract], 36891747, 23144459)

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
An atypically mild case of ethylmalonic encephalopathy with pathogenic ETHE1 variant.	Kashima DT	American journal of medical genetics. Part A	2023	PMID: 36891747
Ethylmalonic Encephalopathy.	Adam MP	-	2017	PMID: 28933811

Text-mined citations for rs763799125 ...

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 Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_014297.5(ETHE1):c.586G>A (p.Asp196Asn)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs763799125 ...