VCV000431797.19 - ClinVar

NM_020928.2(ZSWIM6):c.2737C>T (p.Arg913Ter)

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.

(9)

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/Likely 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_020928.2(ZSWIM6):c.2737C>T (p.Arg913Ter)

Variation ID: 431797 Accession: VCV000431797.19

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 5q12.1 5: 61541917 (GRCh38) [ NCBI UCSC ] 5: 60837744 (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 13, 2018	Aug 25, 2024	Apr 29, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_020928.2:c.2737C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_065979.1:p.Arg913Ter	nonsense
NC_000005.10:g.61541917C>T
NC_000005.9:g.60837744C>T
NG_053150.1:g.214645C>T

Protein change

R913*

Other names

Canonical SPDI

NC_000005.10:61541916: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

ClinGen: CA359946038 OMIM: 615951.0002 dbSNP: rs1554041295 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.
ZSWIM6		-	-	GRCh38 GRCh37	817	839

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.
ZSWIM6 related intellectual disability	Pathogenic (1)	criteria provided, single submitter	Aug 11, 2017	RCV000590997.1
not provided	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Jan 31, 2023	RCV000760560.14
Neurodevelopmental disorder with movement abnormalities, abnormal gait, and autistic features	Pathogenic/Likely pathogenic (4)	criteria provided, multiple submitters, no conflicts	-	RCV000578491.6
ZSWIM6-related disorder	Pathogenic (1)	criteria provided, single submitter	Apr 29, 2023	RCV003403147.4

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 (Aug 11, 2017)	criteria provided, single submitter (Submitter's publication) Method: research	ZSWIM6 related intellectual disability (Autosomal dominant inheritance) Affected status: yes Allele origin: de novo	Sydney Children's Hospital, SCHN Accession: SCV000588874.2 First in ClinVar: Mar 26, 2018 Last updated: Mar 26, 2018	Publications: PubMed (1) PubMed: 29198722 Comment: De novo. Recurrent in 7 individuals with overlapping neurocognitive phenotype. Gene expressed in brain and role in neurodevelopment and function. Number of individuals with the variant: 7 Clinical Features: Intellectual disability, severe (present) Age: 3-21 years Sex: mixed Ethnicity/Population group: Caucasian Geographic origin: United States, UK, Australia Method: exome and genome sequencing, sanger sequencing confirmation
Likely pathogenic (-)	criteria provided, single submitter (ACGS Guidelines, 2016) Method: clinical testing	Neurodevelopmental disorder with movement abnormalities, abnormal gait, and autistic features Affected status: yes Allele origin: germline	Genomics England Pilot Project, Genomics England Accession: SCV001760164.1 First in ClinVar: Jul 27, 2021 Last updated: Jul 27, 2021
Pathogenic (Jan 31, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000890451.4 First in ClinVar: Mar 19, 2019 Last updated: Nov 11, 2023	Comment: Published functional studies demonstrate a dominant-negative effect on the protein (Palmer et al., 2017); Not observed in large population cohorts (gnomAD); Nonsense variant predicted to … (more) Published functional studies demonstrate a dominant-negative effect on the protein (Palmer et al., 2017); Not observed in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation as the last 303 amino acids are lost; This variant is associated with the following publications: (PMID: 29198722, 33958584, 34758253) (less)
Pathogenic (Aug 04, 2018)	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: SCV000958315.4 First in ClinVar: Aug 13, 2019 Last updated: Feb 14, 2024	Publications: PubMed (1) PubMed: 29198722 Comment: This sequence change creates a premature translational stop signal (p.Arg913) in the ZSWIM6 gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Arg913) in the ZSWIM6 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). For these reasons, this variant has been classified as Pathogenic. The current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in ZSWIM6 cause disease. This variant has been observed to be likely or confirmed de novo in multiple individuals affected with severe-profound intellectual disability/developmental delay and additional neurological features, but without frontonasal or limb malformations¬†(PMID: 29198722, Invitae). ClinVar contains an entry for this variant (Variation ID:¬†431797). Experimental studies have shown that this nonsense change does not trigger nonsense-mediated decay of the ZSWIM6 mRNA. This suggests a truncated ZSWIM6 protein lacking the Sin3-like domain exists, which may have a dominant-negative effect.¬†(PMID: 29198722). (less)
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Neurodevelopmental disorder with movement abnormalities, abnormal gait, and autistic features Affected status: yes Allele origin: germline	Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn Accession: SCV002822873.1 First in ClinVar: Jan 21, 2023 Last updated: Jan 21, 2023
Pathogenic (Apr 29, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	ZSWIM6-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004104534.1 First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023	Comment: The ZSWIM6 c.2737C>T variant is predicted to result in premature protein termination (p.Arg913). This variant has been reported as a recurrent de novo variant in … (more) The ZSWIM6 c.2737C>T variant is predicted to result in premature protein termination (p.Arg913). This variant has been reported as a recurrent de novo variant in multiple patients with syndromic intellectual disability (see for example - Palmer et al. 2017. PubMed ID: 29198722). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is located in the penultimate exon and functional studies found it does not undergo nonsense mediated decay and may act in a dominant-negative manner (Palmer et al. 2017. PubMed ID: 29198722). This variant is interpreted as pathogenic. (less)
Pathogenic (May 27, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, Skane University Hospital Lund Accession: SCV005199033.1 First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024
Pathogenic (Feb 09, 2018)	no assertion criteria provided Method: literature only	NEURODEVELOPMENTAL DISORDER WITH MOVEMENT ABNORMALITIES, ABNORMAL GAIT, AND AUTISTIC FEATURES Affected status: not provided Allele origin: germline	OMIM Accession: SCV000680486.1 First in ClinVar: Feb 13, 2018 Last updated: Feb 13, 2018	Publications: PubMed (1) PubMed: 29198722 Comment on evidence: In 7 unrelated patients with neurodevelopmental disorder with movement abnormalities, abnormal gait, and autistic features (NEDMAGA; 617865), Palmer et al. (2017) identified a de novo … (more) In 7 unrelated patients with neurodevelopmental disorder with movement abnormalities, abnormal gait, and autistic features (NEDMAGA; 617865), Palmer et al. (2017) identified a de novo heterozygous c.2737C-T transition (c.2737C-T, NM_020928.1) in exon 13 of the ZSWIM6 gene, resulting in an arg913-to-ter (R913X) substitution. The mutations, which were found by whole-exome or whole-genome sequencing, were confirmed by Sanger sequencing. The mutation was confirmed to occur de novo in 6 patients; paternal DNA was unavailable for 1 patient. The mutation was not found in the gnomAD database. Analysis of patient cells indicated that the mutant transcript escaped nonsense-mediated mRNA decay, and most likely produced a truncated protein, although antibody studies were unable to detect a truncated protein. The mutation was predicted to produce a ZSWIM6 variant lacking the SIN3-like domain. Additional functional studies of the variant were not performed, but Palmer et al. (2017) postulated a dominant-negative effect. (less)
Pathogenic (May 13, 2021)	no assertion criteria provided Method: clinical testing	Neurodevelopmental disorder with movement abnormalities, abnormal gait, and autistic features Affected status: yes Allele origin: de novo	Pediatric Genetics Clinic, Sheba Medical Center Accession: SCV001712257.1 First in ClinVar: Dec 12, 2021 Last updated: Dec 12, 2021	Clinical Features: Global developmental delay (present) , Congenital laryngomalacia (present) , Inguinal hernia (present) , Failure to thrive (present) , Bruxism (present) , Prominent fingertip pads (present) Secondary finding: no

Comment:

Published functional studies demonstrate a dominant-negative effect on the protein (Palmer et al., 2017); Not observed in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation as the last 303 amino acids are lost; This variant is associated with the following publications: (PMID: 29198722, 33958584, 34758253)

Comment:

This sequence change creates a premature translational stop signal (p.Arg913*) in the ZSWIM6 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). For these reasons, this variant has been classified as Pathogenic. The current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in ZSWIM6 cause disease. This variant has been observed to be likely or confirmed de novo in multiple individuals affected with severe-profound intellectual disability/developmental delay and additional neurological features, but without frontonasal or limb malformations¬†(PMID: 29198722, Invitae). ClinVar contains an entry for this variant (Variation ID:¬†431797). Experimental studies have shown that this nonsense change does not trigger nonsense-mediated decay of the ZSWIM6 mRNA. This suggests a truncated ZSWIM6 protein lacking the Sin3-like domain exists, which may have a dominant-negative effect.¬†(PMID: 29198722).

Comment:

The ZSWIM6 c.2737C>T variant is predicted to result in premature protein termination (p.Arg913*). This variant has been reported as a recurrent de novo variant in multiple patients with syndromic intellectual disability (see for example - Palmer et al. 2017. PubMed ID: 29198722). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is located in the penultimate exon and functional studies found it does not undergo nonsense mediated decay and may act in a dominant-negative manner (Palmer et al. 2017. PubMed ID: 29198722). This variant is interpreted as pathogenic.

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
A Recurrent De Novo Nonsense Variant in ZSWIM6 Results in Severe Intellectual Disability without Frontonasal or Limb Malformations.	Palmer EE	American journal of human genetics	2017	PMID: 29198722

Text-mined citations for rs1554041295 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_020928.2(ZSWIM6):c.2737C>T (p.Arg913Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1554041295 ...