VCV001703337.7 - ClinVar

NM_004247.4(EFTUD2):c.1705C>T (p.Arg569Ter)

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.

(3)

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_004247.4(EFTUD2):c.1705C>T (p.Arg569Ter)

Variation ID: 1703337 Accession: VCV001703337.7

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 17q21.31 17: 44860446 (GRCh38) [ NCBI UCSC ] 17: 42937814 (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	Sep 3, 2022	Feb 14, 2024	Apr 20, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_004247.4:c.1705C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_004238.3:p.Arg569Ter	nonsense
NM_001142605.2:c.1600C>T	NP_001136077.1:p.Arg534Ter	nonsense
NM_001258353.2:c.1705C>T	NP_001245282.1:p.Arg569Ter	nonsense
NM_001258354.2:c.1675C>T	NP_001245283.1:p.Arg559Ter	nonsense
NC_000017.11:g.44860446G>A
NC_000017.10:g.42937814G>A
NG_032674.1:g.44180C>T

... more HGVS ... less HGVS

Protein change

R534*, R559*, R569*

Other names

Canonical SPDI

NC_000017.11:44860445:G:A

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

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.
EFTUD2		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	682	695

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.
not provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Oct 10, 2022	RCV002280459.5
Mandibulofacial dysostosis-microcephaly syndrome	Pathogenic (1)	criteria provided, single submitter	Apr 20, 2023	RCV003223434.2

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 (May 09, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV002568585.2 First in ClinVar: Sep 03, 2022 Last updated: Mar 04, 2023	Comment: Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation or nonsense-mediated decay in a gene for … (more) Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation or nonsense-mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 26507355, 33247512, 32410215, 23188108) (less)
Pathogenic (Apr 20, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Mandibulofacial dysostosis-microcephaly syndrome Affected status: yes Allele origin: unknown	Duke University Health System Sequencing Clinic, Duke University Health System Accession: SCV003918985.1 First in ClinVar: Apr 30, 2023 Last updated: Apr 30, 2023
Pathogenic (Oct 10, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003442392.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024	Publications: PubMed (4) PubMed: 23188108‚ 32410215‚ 24999515‚ 26507355 Comment: For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 1703337). This premature translational stop signal … (more) For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 1703337). This premature translational stop signal has been observed in individual(s) with EFTUD2-related conditions (PMID: 23188108, 32410215). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg569*) in the EFTUD2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in EFTUD2 are known to be pathogenic (PMID: 24999515, 26507355). (less)

Comment:

Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation or nonsense-mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 26507355, 33247512, 32410215, 23188108)

Comment:

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 1703337). This premature translational stop signal has been observed in individual(s) with EFTUD2-related conditions (PMID: 23188108, 32410215). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg569*) in the EFTUD2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in EFTUD2 are known to be pathogenic (PMID: 24999515, 26507355).

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
Mandibulofacial Dysostosis with Microcephaly.	Adam MP	-	2023	PMID: 24999515
Prenatal exome sequencing in fetuses with congenital heart defects.	Li R	Clinical genetics	2020	PMID: 32410215
Mandibulofacial Dysostosis with Microcephaly: Mutation and Database Update.	Huang L	Human mutation	2016	PMID: 26507355
EFTUD2 haploinsufficiency leads to syndromic oesophageal atresia.	Gordon CT	Journal of medical genetics	2012	PMID: 23188108

Text-mined citations for this variant ...

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_004247.4(EFTUD2):c.1705C>T (p.Arg569Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...