VCV000155772.20 - ClinVar

NM_020928.2(ZSWIM6):c.3487C>T (p.Arg1163Trp)

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.3487C>T (p.Arg1163Trp)

Variation ID: 155772 Accession: VCV000155772.20

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 5q12.1 5: 61544156 (GRCh38) [ NCBI UCSC ] 5: 60839983 (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 29, 2015	Oct 20, 2024	Nov 10, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_020928.2:c.3487C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_065979.1:p.Arg1163Trp	missense
NC_000005.10:g.61544156C>T
NC_000005.9:g.60839983C>T
NG_053150.1:g.216884C>T
	Q9HCJ5:p.Arg1163Trp

... more HGVS ... less HGVS

Protein change

R1163W

Other names

Canonical SPDI

NC_000005.10:61544155: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: CA170707 UniProtKB: Q9HCJ5#VAR_071802 OMIM: 615951.0001 dbSNP: rs587777695 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.
Acromelic frontonasal dysostosis	Pathogenic/Likely pathogenic (6)	criteria provided, multiple submitters, no conflicts	Nov 10, 2023	RCV000143865.11
not provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	May 1, 2023	RCV000478201.16
Inborn genetic diseases	Pathogenic (1)	criteria provided, single submitter	Apr 2, 2017	RCV000624254.3

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 (Sep 23, 2014)	criteria provided, single submitter (submitter's publication) Method: research	Acromelic frontonasal dysostosis Affected status: yes Allele origin: de novo	University of Washington Center for Mendelian Genomics, University of Washington Accession: SCV000246129.1 First in ClinVar: Sep 29, 2015 Last updated: Sep 29, 2015	Publications: PubMed (1) PubMed: 25105228
Pathogenic (Oct 11, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Acromelic frontonasal dysostosis Affected status: yes Allele origin: unknown	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne Study: Clinvar_gadteam_Clinical_exome_analysis_3 Accession: SCV000803852.1 First in ClinVar: Aug 24, 2018 Last updated: Aug 24, 2018
Pathogenic (Apr 13, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000568856.6 First in ClinVar: Apr 27, 2017 Last updated: Mar 04, 2023	Comment: Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more) Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25105228, 33776626, 26706854) (less)
Pathogenic (Nov 10, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Acromelic frontonasal dysostosis Affected status: yes Allele origin: unknown	Daryl Scott Lab, Baylor College of Medicine Accession: SCV004102654.1 First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023
Likely pathogenic (May 31, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	Acromelic frontonasal dysostosis Affected status: unknown Allele origin: unknown	SIB Swiss Institute of Bioinformatics Accession: SCV000803459.1 First in ClinVar: Feb 13, 2018 Last updated: Feb 13, 2018	Publications: PubMed (2) PubMed: 25105228‚ 26706854 Comment: This variant is interpreted as a Likely Pathogenic, for Acromelic frontonasal dysostosis, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: PM6 => Assumed … (more) This variant is interpreted as a Likely Pathogenic, for Acromelic frontonasal dysostosis, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: PM6 => Assumed de novo, but without confirmation of paternity and maternity (PMID:25105228). PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS4-Moderate => Observed in multiple unrelated patients. (PMID:25105228,26706854). (less)
Pathogenic (Apr 02, 2017)	criteria provided, single submitter (Ambry exome assertion method (8-5-2015)) Method: clinical testing	Inborn genetic diseases Affected status: yes Allele origin: germline	Ambry Genetics Accession: SCV000742103.3 First in ClinVar: Apr 15, 2018 Last updated: Jan 07, 2023	Number of individuals with the variant: 1 Clinical Features: Tetralogy of Fallot (present) , Global developmental delay (present) , Generalized hypotonia (present) , Abnormality of the parietal bone (present) , Feeding difficulties (present) , … (more) Tetralogy of Fallot (present) , Global developmental delay (present) , Generalized hypotonia (present) , Abnormality of the parietal bone (present) , Feeding difficulties (present) , Short stature (present) , Micropenis (present) , Cryptorchidism (present) , Small scrotum (present) , Strabismus (present) , Scoliosis (present) , Corpus callosum, agenesis of (present) , Hypertelorism (present) , Telecanthus (present) , Bifid nasal tip (present) , Depressed nasal tip (present) , Broad columella (present) , Abnormality of the external nose (present) , Low-set ears (present) , Lop ear (present) , High palate (present) , Abnormality of the uvula (present) , Parietal foramina (present) (less) Sex: male Ethnicity/Population group: Hispanic
Pathogenic (May 01, 2023)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV004011595.12 First in ClinVar: Jul 16, 2023 Last updated: Oct 20, 2024	Comment: ZSWIM6: PS2:Very Strong, PM2, PP2, PS3:Supporting Number of individuals with the variant: 1
Pathogenic (Aug 07, 2014)	no assertion criteria provided Method: literature only	ACROMELIC FRONTONASAL DYSOSTOSIS Affected status: not provided Allele origin: germline	OMIM Accession: SCV000188733.3 First in ClinVar: Sep 08, 2014 Last updated: Feb 13, 2018	Publications: PubMed (2) PubMed: 25105228‚ 26706854 Comment on evidence: In 4 unrelated patients with acromelic frontonasal dysostosis (AFND; 603671), Smith et al. (2014) identified heterozygosity for a de novo c.3487C-T transition in exon 14 … (more) In 4 unrelated patients with acromelic frontonasal dysostosis (AFND; 603671), Smith et al. (2014) identified heterozygosity for a de novo c.3487C-T transition in exon 14 of the ZSWIM6 gene, resulting in an arg1163-to-trp (R1163W) substitution at a highly conserved residue in the SIN3-like domain. In the most mildly affected patient, the mutation was present at a 60:40 ratio of wildtype to mutant allele, suggestive of mosaicism. In 2 sporadic patients with AFND and the severely affected son of a mildly affected woman, Twigg et al. (2016) identified heterozygosity for the R1163W mutation in the ZSWIM6 gene. Deep sequencing of DNA in 5 tissues from the mildly affected mother confirmed mosaicism for the mutation, with the variant allele being present at approximately 11% in buccal scrapings, 3% in saliva, 2% in urine and blood, and 1% in skin. (less)
not provided (-)	no classification provided Method: phenotyping only	Acromelic frontonasal dysostosis Affected status: unknown Allele origin: unknown	GenomeConnect, ClinGen Accession: SCV000986913.1 First in ClinVar: Aug 30, 2019 Last updated: Aug 30, 2019	Comment: Variant interpretted as pathogenic and reported on 09/20/2018 by GTR ID 239772. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from … (more) Variant interpretted as pathogenic and reported on 09/20/2018 by GTR ID 239772. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less) Clinical Features: Oral cleft (present) , Abnormal facial shape (present) , Abnormality of the hair (present) , Abnormality of the mouth (present) , Abnormality of the nose … (more) Oral cleft (present) , Abnormal facial shape (present) , Abnormality of the hair (present) , Abnormality of the mouth (present) , Abnormality of the nose (present) , Abnormality of the skull (present) , Abnormality of the nervous system (present) , Abnormality of the foot (present) , Abnormality of cardiovascular system morphology (present) (less) Sex: female Testing laboratory: PreventionGenetics,PreventionGenetics Date variant was reported to submitter: 2018-09-20 Testing laboratory interpretation: Pathogenic

Comment:

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25105228, 33776626, 26706854)

Comment:

This variant is interpreted as a Likely Pathogenic, for Acromelic frontonasal dysostosis, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: PM6 => Assumed de novo, but without confirmation of paternity and maternity (PMID:25105228). PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS4-Moderate => Observed in multiple unrelated patients. (PMID:25105228,26706854).

Comment:

Variant interpretted as pathogenic and reported on 09/20/2018 by GTR ID 239772. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

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
Acromelic frontonasal dysostosis and ZSWIM6 mutation: phenotypic spectrum and mosaicism.	Twigg SR	Clinical genetics	2016	PMID: 26706854
Exome sequencing identifies a recurrent de novo ZSWIM6 mutation associated with acromelic frontonasal dysostosis.	Smith JD	American journal of human genetics	2014	PMID: 25105228

Text-mined citations for rs587777695 ...

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 Oct 20, 2024

ClinVar Genomic variation as it relates to human health

NM_020928.2(ZSWIM6):c.3487C>T (p.Arg1163Trp)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs587777695 ...