VCV001805634.4 - ClinVar

NM_001130053.5(EEF1D):c.1753C>T (p.Arg585Cys)

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.

Uncertain significance

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001130053.5(EEF1D):c.1753C>T (p.Arg585Cys)

Variation ID: 1805634 Accession: VCV001805634.4

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 8q24.3 8: 143580164 (GRCh38) [ NCBI UCSC ] 8: 144662334 (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	Dec 24, 2022	Nov 10, 2024	Mar 12, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001130053.5:c.1753C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001123525.3:p.Arg585Cys	missense
NM_001130055.4:c.655C>T	NP_001123527.1:p.Arg219Cys	missense
NM_001130056.5:c.583C>T	NP_001123528.1:p.Arg195Cys	missense
NM_001130057.4:c.655C>T	NP_001123529.1:p.Arg219Cys	missense
NM_001195203.4:c.598C>T	NP_001182132.1:p.Arg200Cys	missense
NM_001289950.4:c.655C>T	NP_001276879.1:p.Arg219Cys	missense
NM_001317743.4:c.583C>T	NP_001304672.1:p.Arg195Cys	missense
NM_001330646.3:c.583C>T	NP_001317575.1:p.Arg195Cys	missense
NM_001960.7:c.655C>T	NP_001951.2:p.Arg219Cys	missense
NM_032378.4:c.1753C>T
NM_032378.7:c.1753C>T	NP_115754.4:p.Arg585Cys	missense
NC_000008.11:g.143580164G>A
NC_000008.10:g.144662334G>A

... more HGVS ... less HGVS

Protein change

R195C, R200C, R219C, R585C

Other names

Canonical SPDI

NC_000008.11:143580163: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.
EEF1D		-	-	GRCh38 GRCh38 GRCh37	95	155

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.
Neurodevelopmental disorder	Uncertain significance (1)	criteria provided, single submitter	May 25, 2020	RCV002472052.1
not specified	Uncertain significance (1)	criteria provided, single submitter	Mar 31, 2023	RCV004067595.1
not provided	Uncertain significance (1)	criteria provided, single submitter	Mar 12, 2024	RCV004779354.1

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.
Uncertain significance (May 25, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Neurodevelopmental disorder (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV002768410.1 First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022	Publications: PubMed (2) PubMed: 28097321‚ 30787422 Comment: Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as 3A-VUS. Following criteria are met: 0105 - The mechanism of disease for this gene … (more) Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as 3A-VUS. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established, however it is suspected to be loss-of-function (PMID: 30787422; PMID: 28097321). (N) 0106 - This gene is known to be associated with autosomal recessive disease (PMID: 30787422; PMID: 28097321). (N) 0200 - Variant is predicted to result in a missense amino acid change from an arginine to a cysteine (exon 9). (N) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (18 heterozygotes, 0 homozygotes). (P) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (45 heterozygotes, 0 homozygotes). (N) 0501 - Missense variant consistently predicted to be damaging by multiple in-silico tools or highly conserved with a major amino acid change. (P) 0600 - Variant is located in an annotated domain or motif (EF-1 guanine nucleotide exchange domain; NCBI, Decipher, PDB). (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0807 - Variant has not previously been reported in a clinical context. (N) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1201 - Heterozygous variant detected in trans with a second likely pathogenic heterozygous variant in a recessive disease. (P) 1205 - Variant is maternally inherited. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign (less)
Uncertain significance (Mar 31, 2023)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV003950912.2 First in ClinVar: Jul 08, 2023 Last updated: May 01, 2024	Comment: The c.1753C>T (p.R585C) alteration is located in exon 9 (coding exon 7) of the EEF1D gene. This alteration results from a C to T substitution … (more) The c.1753C>T (p.R585C) alteration is located in exon 9 (coding exon 7) of the EEF1D gene. This alteration results from a C to T substitution at nucleotide position 1753, causing the arginine (R) at amino acid position 585 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. (less)
Uncertain significance (Mar 12, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV005389449.1 First in ClinVar: Nov 10, 2024 Last updated: Nov 10, 2024	Comment: In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to … (more) In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge (less)

Comment:

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as 3A-VUS. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established, however it is suspected to be loss-of-function (PMID: 30787422; PMID: 28097321). (N) 0106 - This gene is known to be associated with autosomal recessive disease (PMID: 30787422; PMID: 28097321). (N) 0200 - Variant is predicted to result in a missense amino acid change from an arginine to a cysteine (exon 9). (N) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (18 heterozygotes, 0 homozygotes). (P) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (45 heterozygotes, 0 homozygotes). (N) 0501 - Missense variant consistently predicted to be damaging by multiple in-silico tools or highly conserved with a major amino acid change. (P) 0600 - Variant is located in an annotated domain or motif (EF-1 guanine nucleotide exchange domain; NCBI, Decipher, PDB). (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0807 - Variant has not previously been reported in a clinical context. (N) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1201 - Heterozygous variant detected in trans with a second likely pathogenic heterozygous variant in a recessive disease. (P) 1205 - Variant is maternally inherited. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign

Comment:

The c.1753C>T (p.R585C) alteration is located in exon 9 (coding exon 7) of the EEF1D gene. This alteration results from a C to T substitution at nucleotide position 1753, causing the arginine (R) at amino acid position 585 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

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
Biallelic loss of EEF1D function links heat shock response pathway to autosomal recessive intellectual disability.	Ugur Iseri SA	Journal of human genetics	2019	PMID: 30787422
Diagnostic Yield and Novel Candidate Genes by Exome Sequencing in 152 Consanguineous Families With Neurodevelopmental Disorders.	Reuter MS	JAMA psychiatry	2017	PMID: 28097321

Text-mined citations for this variant ...

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_001130053.5(EEF1D):c.1753C>T (p.Arg585Cys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...