VCV000584445.7 - ClinVar

NM_016628.5(WAC):c.1537C>T (p.Arg513Ter)

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.

(6)

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_016628.5(WAC):c.1537C>T (p.Arg513Ter)

Variation ID: 584445 Accession: VCV000584445.7

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 10p12.1 10: 28614666 (GRCh38) [ NCBI UCSC ] 10: 28903595 (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	Oct 10, 2018	Nov 24, 2024	Sep 20, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_016628.5:c.1537C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_057712.2:p.Arg513Ter	nonsense
NM_100264.3:c.1402C>T	NP_567822.1:p.Arg468Ter	nonsense
NM_100486.4:c.1228C>T	NP_567823.1:p.Arg410Ter	nonsense
NC_000010.11:g.28614666C>T
NC_000010.10:g.28903595C>T
NG_046603.1:g.87079C>T

... more HGVS ... less HGVS

Protein change

R513*, R468*, R410*

Other names

Canonical SPDI

NC_000010.11:28614665:C:T

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

dbSNP: rs1564421528 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.
WAC		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	284	316

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.
DeSanto-Shinawi syndrome due to WAC point mutation	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Sep 20, 2024	RCV000708579.4
not provided	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Dec 5, 2022	RCV001269613.4

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.
Pathogenic (Mar 05, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	DeSanto-Shinawi syndrome due to WAC point mutation (Autosomal dominant inheritance) Affected status: yes Allele origin: de novo	Undiagnosed Diseases Network, NIH Study: Undiagnosed Diseases Network (NIH), UDN Accession: SCV000837703.1 First in ClinVar: Oct 10, 2018 Last updated: Oct 10, 2018	Number of individuals with the variant: 1 Clinical Features: Wide nasal bridge (present) , Unilateral ptosis (present) , Sleep disturbance (present) , Short nose (present) , Secondary Caesarian section (present) , Premature birth (present) … (more) Wide nasal bridge (present) , Unilateral ptosis (present) , Sleep disturbance (present) , Short nose (present) , Secondary Caesarian section (present) , Premature birth (present) , Neonatal hypoglycemia (present) , Moderate global developmental delay (present) , Feeding difficulties (present) , Epicanthus (present) , Constipation (present) , Caesarian section (present) , Broad nasal tip (present) , Adrenal insufficiency (present) , Absent speech (present) , Abnormal delivery (present) (less) Age: 0-9 years Sex: female Ethnicity/Population group: African American Testing laboratory: Baylor Genetics Date variant was reported to submitter: 2018-03-05 Testing laboratory interpretation: Pathogenic
Pathogenic (Mar 28, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics and Genomics, Karolinska University Hospital Accession: SCV001449718.1 First in ClinVar: Dec 11, 2020 Last updated: Dec 11, 2020	Number of individuals with the variant: 1
Pathogenic (Dec 05, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV002762316.1 First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 2022	Comment: Previously reported as p.Arg468* (Frisk et al., 2022); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which … (more) Previously reported as p.Arg468* (Frisk et al., 2022); 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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 35118825, 33726816) (less)
Pathogenic (Sep 20, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	DeSanto-Shinawi syndrome due to WAC point mutation (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV005086122.2 First in ClinVar: Jul 23, 2024 Last updated: Nov 24, 2024	Comment: Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more) Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Desanto-Shinawi syndrome (MIM#616708). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Many other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical laboratories in ClinVar and LOVD and has been observed in a de novo individual in DECIPHER. (SP) 1007 - No published functional evidence has been identified for this variant. (I) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV002034898.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, Amsterdam University Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV002035264.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021

Comment:

Previously reported as p.Arg468* (Frisk et al., 2022); 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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 35118825, 33726816)

Comment:

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Desanto-Shinawi syndrome (MIM#616708). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Many other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical laboratories in ClinVar and LOVD and has been observed in a de novo individual in DECIPHER. (SP) 1007 - No published functional evidence has been identified for this variant. (I) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

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

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for rs1564421528 ...

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 Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_016628.5(WAC):c.1537C>T (p.Arg513Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1564421528 ...