VCV002204087.4 - ClinVar

NM_001136157.2(OTUD5):c.1543C>T (p.Arg515Trp)

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.

Conflicting classifications of pathogenicity
Likely pathogenic(2); Uncertain significance(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001136157.2(OTUD5):c.1543C>T (p.Arg515Trp)

Variation ID: 2204087 Accession: VCV002204087.4

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: Xp11.23 X: 48923669 (GRCh38) [ NCBI UCSC ] X: 48780946 (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, 2023	May 1, 2024	Feb 23, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_001136157.2:c.1543C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001129629.1:p.Arg515Trp	missense
NM_001136158.2:c.1543C>T	NP_001129630.1:p.Arg515Trp	missense
NM_001136159.2:c.892C>T	NP_001129631.1:p.Arg298Trp	missense
NM_017602.4:c.1558C>T	NP_060072.1:p.Arg520Trp	missense
NC_000023.11:g.48923669G>A
NC_000023.10:g.48780946G>A
NG_016262.2:g.468C>T
NG_146905.1:g.267G>A

... more HGVS ... less HGVS

Protein change

R520W, R298W, R515W

Other names

Canonical SPDI

NC_000023.11:48923668: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.
OTUD5		-	-	GRCh38 GRCh38 GRCh37	57	228

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.
Multiple congenital anomalies-neurodevelopmental syndrome, X-linked	Likely pathogenic (1)	criteria provided, single submitter	Feb 23, 2023	RCV003152813.3
not provided	Uncertain significance (1)	criteria provided, single submitter	May 20, 2022	RCV003321977.2
Inborn genetic diseases	Likely pathogenic (1)	criteria provided, single submitter	Jan 3, 2022	RCV002668106.4

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.
Likely pathogenic (Jan 03, 2022)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV003534005.2 First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024	Publications: PubMed (1) PubMed: 33523931 Comment: The c.1558C>T (p.R520W) alteration is located in exon 8 (coding exon 8) of the OTUD5 gene. This alteration results from a C to T substitution … (more) The c.1558C>T (p.R520W) alteration is located in exon 8 (coding exon 8) of the OTUD5 gene. This alteration results from a C to T substitution at nucleotide position 1558, causing the arginine (R) at amino acid position 520 to be replaced by a tryptophan (W). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration was reported de novo in one individual with global developmental delay, moderate intellectual disability, autistic behavior, hirsutism, macrocephaly, central nervous system abnormalities, feeding difficulties, hepatomegaly, conductive hearing loss, hypermetropia, astigmatism, hypodontia, butterfly vertebrae, duplex left kidney, low folate, and dysmorphic features (Beck, 2021). This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). This alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. (less)
Likely pathogenic (Feb 23, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Multiple congenital anomalies-neurodevelopmental syndrome, X-linked Affected status: yes Allele origin: unknown	3billion Accession: SCV003841589.1 First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023	Publications: PubMed (1) PubMed: 33523931 Comment: The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. Same nucleotide change resulting in same amino acid … (more) The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. Same nucleotide change resulting in same amino acid change has been previously reported to be associated with OTUD5-related disorder (PMID: 33523931). The variant has been previously reported as de novo in a similarly affected individual (PMID: 33523931, 33523931). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Global developmental delay (present) , Febrile seizure (within the age range of 3 months to 6 years) (present) , Delayed ability to walk (present) , … (more) Global developmental delay (present) , Febrile seizure (within the age range of 3 months to 6 years) (present) , Delayed ability to walk (present) , Abnormal facial shape (present) (less)
Uncertain significance (May 20, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden Accession: SCV004026041.1 First in ClinVar: Aug 19, 2023 Last updated: Aug 19, 2023	Comment: PP3, PM2_SUP, PP2

Comment:

The c.1558C>T (p.R520W) alteration is located in exon 8 (coding exon 8) of the OTUD5 gene. This alteration results from a C to T substitution at nucleotide position 1558, causing the arginine (R) at amino acid position 520 to be replaced by a tryptophan (W). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration was reported de novo in one individual with global developmental delay, moderate intellectual disability, autistic behavior, hirsutism, macrocephaly, central nervous system abnormalities, feeding difficulties, hepatomegaly, conductive hearing loss, hypermetropia, astigmatism, hypodontia, butterfly vertebrae, duplex left kidney, low folate, and dysmorphic features (Beck, 2021). This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). This alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic.

Comment:

The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. Same nucleotide change resulting in same amino acid change has been previously reported to be associated with OTUD5-related disorder (PMID: 33523931). The variant has been previously reported as de novo in a similarly affected individual (PMID: 33523931, 33523931). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.

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
Linkage-specific deubiquitylation by OTUD5 defines an embryonic pathway intolerant to genomic variation.	Beck DB	Science advances	2021	PMID: 33523931

Text-mined citations for this variant ...

Record last updated May 01, 2024

ClinVar Genomic variation as it relates to human health

NM_001136157.2(OTUD5):c.1543C>T (p.Arg515Trp)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...