ClinVar Genomic variation as it relates to human health
NM_018127.7(ELAC2):c.2342G>A (p.Arg781His)
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.
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(2); Likely pathogenic(2); Uncertain significance(4)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_018127.7(ELAC2):c.2342G>A (p.Arg781His)
Variation ID: 5058 Accession: VCV000005058.30
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17p12 17: 12992957 (GRCh38) [ NCBI UCSC ] 17: 12896274 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 12, 2024 Mar 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_018127.7:c.2342G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_060597.4:p.Arg781His missense NM_001165962.2:c.2222G>A NP_001159434.1:p.Arg741His missense NM_173717.2:c.2339G>A NP_776065.1:p.Arg780His missense NC_000017.11:g.12992957C>T NC_000017.10:g.12896274C>T NG_015808.1:g.30108G>A Q9BQ52:p.Arg781His - Protein change
- R781H, R741H, R780H
- Other names
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- Canonical SPDI
- NC_000017.11:12992956:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe 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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
1000 Genomes Project 30x 0.00031
Trans-Omics for Precision Medicine (TOPMed) 0.00047
Exome Aggregation Consortium (ExAC) 0.00051
The Genome Aggregation Database (gnomAD) 0.00064
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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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
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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. |
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ELAC2 | - | - |
GRCh38 GRCh37 |
1001 | 1017 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (1) |
no assertion criteria provided
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Feb 1, 2001 | RCV000005361.4 | |
Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
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Jan 25, 2024 | RCV000470586.21 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Mar 1, 2024 | RCV000523886.18 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jul 30, 2021 | RCV002512804.2 |
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
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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
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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
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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. |
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Uncertain significance
(Sep 01, 2017)
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criteria provided, single submitter
Method: clinical testing
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Combined oxidative phosphorylation defect type 17
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Baylor Genetics
Accession: SCV000807604.2
First in ClinVar: Feb 08, 2018 Last updated: Dec 11, 2022 |
Comment:
This mutation has been previously reported in association with prostate cancer. It was found twice in our laboratory in trans with loss-of-function mutations: in a … (more)
This mutation has been previously reported in association with prostate cancer. It was found twice in our laboratory in trans with loss-of-function mutations: in a 1-year-old male with global delays, hypotonia, dysmorphism, microcephaly, failure to thrive, hypertorphic cardiomyopathy requiring transplant, and abnormal respiratory chain studies; in a 2-year-old female with global delays, hearing loss, hypotonia, dysmorphism, short stature, hypertrophic cardiomyopathy, delayed myelination. Heterozygotes would be expected to be asymptomatic carriers. (less)
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Uncertain significance
(Jan 17, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: unknown
Allele origin:
germline
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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV000802218.2
First in ClinVar: Aug 04, 2018 Last updated: Jan 26, 2024 |
Comment:
PM3
Number of individuals with the variant: 6
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Uncertain significance
(Apr 09, 2020)
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criteria provided, single submitter
Method: clinical testing
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Combined oxidative phosphorylation defect type 17
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV003831880.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 25, 2024)
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criteria provided, single submitter
Method: clinical testing
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Combined oxidative phosphorylation defect type 17
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000559558.7
First in ClinVar: Apr 17, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 781 of the ELAC2 protein (p.Arg781His). … (more)
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 781 of the ELAC2 protein (p.Arg781His). This variant is present in population databases (rs119484086, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of ELAC2-related conditions (PMID: 31045291; Invitae; external communication). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 5058). 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 ELAC2 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Mar 01, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV004142276.5
First in ClinVar: Nov 20, 2023 Last updated: May 12, 2024 |
Comment:
ELAC2: PM3:Strong, PM2
Number of individuals with the variant: 3
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Pathogenic
(Nov 16, 2017)
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criteria provided, single submitter
Method: clinical testing
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Combined oxidative phosphorylation defect type 17
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
maternal
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Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV000680207.1
First in ClinVar: Feb 08, 2018 Last updated: Feb 08, 2018 |
Sex: female
Tissue: blood
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Likely pathogenic
(May 26, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000616709.7
First in ClinVar: Dec 19, 2017 Last updated: Jul 01, 2023 |
Comment:
Observed as heterozygous and segregating with disease in a single family with prostate cancer (Tavtigian et a., 2001); Published functional studies are contradictory: some suggesting … (more)
Observed as heterozygous and segregating with disease in a single family with prostate cancer (Tavtigian et a., 2001); Published functional studies are contradictory: some suggesting impaired mitochondrial enzymatic activity of ELAC2, and others suggesting mitochondrial enzymatic activity similar to wildtype (Minagawa et al., 2005; Noda et al., 2006; Saoura et al., 2019); 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: 15892892, 18809514, 24082139, 12515253, 15317868, 12021166, 11175785, 12569551, 19555350, 15593091, 11507049, 12522685, 12790786, 15863270, 12711671, 16636667, 16287462, 25326635, 31045291, 33314036, 34539450, 28569218, 34964002) (less)
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Uncertain significance
(Jul 30, 2021)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV003722580.2
First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024 |
Comment:
(Saoura, 2019) Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
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Pathogenic
(Feb 01, 2001)
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no assertion criteria provided
Method: literature only
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PROSTATE CANCER, HEREDITARY, 2
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000025539.3
First in ClinVar: Apr 04, 2013 Last updated: Feb 03, 2020 |
Comment on evidence:
In a patient with prostate cancer (HPC2; 614731) diagnosed at the age of 50, Tavtigian et al. (2001) found an arg781-to-his (R781H) mutation in the … (more)
In a patient with prostate cancer (HPC2; 614731) diagnosed at the age of 50, Tavtigian et al. (2001) found an arg781-to-his (R781H) mutation in the ELAC2 gene. The mutation was traced back through 4 generations to a man who had affected descendants from 5 wives. Prostate cancer cases carrying the missense change had been found among the descendants from 3 of these 5 marriages. In addition, a female carrier of the mutation was diagnosed with ovarian cancer at age 43. Within the generations with phenotype information, there were only 2 unaffected males over age 45 who carried the mutation. (less)
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Mutations in ELAC2 associated with hypertrophic cardiomyopathy impair mitochondrial tRNA 3'-end processing. | Saoura M | Human mutation | 2019 | PMID: 31045291 |
The missense mutations in the candidate prostate cancer gene ELAC2 do not alter enzymatic properties of its product. | Minagawa A | Cancer letters | 2005 | PMID: 15863270 |
A candidate prostate cancer susceptibility gene at chromosome 17p. | Tavtigian SV | Nature genetics | 2001 | PMID: 11175785 |
Text-mined citations for rs119484086 ...
HelpRecord last updated May 12, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.