VCV000066037.12 - ClinVar

NM_018127.7(ELAC2):c.460T>C (p.Phe154Leu)

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

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_018127.7(ELAC2):c.460T>C (p.Phe154Leu)

Variation ID: 66037 Accession: VCV000066037.12

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 17p12 17: 13014469 (GRCh38) [ NCBI UCSC ] 17: 12917786 (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 20, 2015	May 7, 2024	Mar 14, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_018127.7:c.460T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_060597.4:p.Phe154Leu	missense
NM_001165962.2:c.460T>C	NP_001159434.1:p.Phe154Leu	missense
NM_173717.2:c.460T>C	NP_776065.1:p.Phe154Leu	missense
NC_000017.11:g.13014469A>G
NC_000017.10:g.12917786A>G
NG_015808.1:g.8596T>C
	Q9BQ52:p.Phe154Leu

... more HGVS ... less HGVS

Protein change

F154L

Other names

F135L
F60L

Canonical SPDI

NC_000017.11:13014468:A:G

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), exomes 0.00000

Exome Aggregation Consortium (ExAC) 0.00001

Links

ClinGen: CA144837 UniProtKB: Q9BQ52#VAR_070844 OMIM: 605367.0008 dbSNP: rs397515465 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.
ELAC2		-	-	GRCh38 GRCh37	1008	1024

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 oxidative phosphorylation defect type 17	Pathogenic (6)	criteria provided, multiple submitters, no conflicts	Mar 11, 2024	RCV000056276.14
Prostate cancer, hereditary, 2, susceptibility to	Pathogenic (1)	criteria provided, single submitter	Mar 14, 2024	RCV004527310.2

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 (Apr 02, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Combined oxidative phosphorylation defect type 17 Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002022178.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Sep 03, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Combined oxidative phosphorylation defect type 17 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003443770.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024	Publications: PubMed (5) PubMed: 23849775‚ 31045291‚ 28441660‚ 28454995‚ 32870709 Comment: For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects ELAC2 function (PMID: 23849775, 31045291). Algorithms … (more) For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects ELAC2 function (PMID: 23849775, 31045291). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 66037). This missense change has been observed in individuals with ELAC2-related conditions (PMID: 23849775, 28441660, 28454995, 31045291, 32870709). This variant is present in population databases (rs397515465, gnomAD 0.0009%). This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 154 of the ELAC2 protein (p.Phe154Leu). (less)
Pathogenic (Mar 11, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Combined oxidative phosphorylation defect type 17 (Autosomal recessive inheritance) Affected status: yes Allele origin: inherited	Centre for Inherited Metabolic Diseases, Karolinska University Hospital Accession: SCV004708218.1 First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024
Pathogenic (Dec 21, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Combined oxidative phosphorylation defect type 17 (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Pediatric/Medical Genetics, Ministry of Health, Qatif Central Hospital Accession: SCV002766595.1 First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022	Age: 0-9 years Sex: male Ethnicity/Population group: Arab
Pathogenic (Mar 14, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Prostate cancer, hereditary, 2, susceptibility to Affected status: unknown Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Accession: SCV005038810.1 First in ClinVar: May 07, 2024 Last updated: May 07, 2024
Pathogenic (Aug 08, 2013)	no assertion criteria provided Method: literature only	COMBINED OXIDATIVE PHOSPHORYLATION DEFICIENCY 17 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000087448.4 First in ClinVar: Oct 10, 2013 Last updated: Jul 07, 2021	Publications: PubMed (1) PubMed: 23849775 Comment on evidence: In a girl, born of consanguineous parents of Arab descent, with combined oxidative phosphorylation deficiency-17 (COXPD17; 615440), Haack et al. (2013) identified a homozygous c.460T-C … (more) In a girl, born of consanguineous parents of Arab descent, with combined oxidative phosphorylation deficiency-17 (COXPD17; 615440), Haack et al. (2013) identified a homozygous c.460T-C transition in exon 5 of the ELAC2 gene, resulting in a phe154-to-leu (F154L) substitution at a conserved residue in a metallo-beta-lactamase superfamily domain. The mutation was found by exome sequencing and was present at less than 0.2% frequency in 1,846 control exomes and public databases. She presented at age 2 months with poor growth, hypertrophic cardiomyopathy, and lactic acidosis, and died at age 11 months. Biochemical studies showed decreased complex I activity (60% of normal) in skeletal muscle, and there was an accumulation of unprocessed mt-tRNA intermediates in fibroblasts that could be rescued by expression of wildtype ELAC2. Family history revealed that a brother had died of unknown case at age 13 days and a sister had died of dilated hypertrophic cardiomyopathy at age 3 months. (less)
Pathogenic (Aug 25, 2019)	no assertion criteria provided Method: clinical testing	Combined oxidative phosphorylation defect type 17 Affected status: yes Allele origin: germline	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City Accession: SCV001132935.1 First in ClinVar: Jan 04, 2020 Last updated: Jan 04, 2020

Comment:

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects ELAC2 function (PMID: 23849775, 31045291). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 66037). This missense change has been observed in individuals with ELAC2-related conditions (PMID: 23849775, 28441660, 28454995, 31045291, 32870709). This variant is present in population databases (rs397515465, gnomAD 0.0009%). This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 154 of the ELAC2 protein (p.Phe154Leu).

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
Categorized Genetic Analysis in Childhood-Onset Cardiomyopathy.	Al-Hassnan ZN	Circulation. Genomic and precision medicine	2020	PMID: 32870709
Mutations in ELAC2 associated with hypertrophic cardiomyopathy impair mitochondrial tRNA 3'-end processing.	Saoura M	Human mutation	2019	PMID: 31045291
A multicenter clinical exome study in unselected cohorts from a consanguineous population of Saudi Arabia demonstrated a high diagnostic yield.	Alfares A	Molecular genetics and metabolism	2017	PMID: 28454995
The Phenotype and Outcome of Infantile Cardiomyopathy Caused by a Homozygous ELAC2 Mutation.	Shinwari ZMA	Cardiology	2017	PMID: 28441660
ELAC2 mutations cause a mitochondrial RNA processing defect associated with hypertrophic cardiomyopathy.	Haack TB	American journal of human genetics	2013	PMID: 23849775

Text-mined citations for rs397515465 ...

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_018127.7(ELAC2):c.460T>C (p.Phe154Leu)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs397515465 ...