VCV003367188.1 - ClinVar

NM_003410.4(ZFX):c.1996_1997del (p.Met666fs)

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.

(1)

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, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_003410.4(ZFX):c.1996_1997del (p.Met666fs)

Variation ID: 3367188 Accession: VCV003367188.1

Type and length

Deletion, 2 bp

Location

Cytogenetic: Xp22.11 X: 24210954-24210955 (GRCh38) [ NCBI UCSC ] X: 24229071-24229072 (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	Nov 3, 2024	Nov 3, 2024	Oct 28, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_003410.4:c.1996_1997del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_003401.2:p.Met666fs	frameshift
NM_001178084.2:c.1996_1997del	NP_001171555.1:p.Met666fs	frameshift
NM_001178085.1:c.1996_1997del	NP_001171556.1:p.Met666fs	frameshift
NM_001178086.2:c.1309_1310del	NP_001171557.1:p.Met437fs	frameshift
NM_001178095.2:c.756_757del		3 prime UTR
NM_001330327.2:c.2113_2114del	NP_001317256.1:p.Met705fs	frameshift
NC_000023.11:g.24210954_24210955del
NC_000023.10:g.24229071_24229072del
NG_021253.2:g.66218_66219del

... more HGVS ... less HGVS

Protein change

M437fs, M666fs, M705fs

Other names

Canonical SPDI

NC_000023.11:24210953:AT:

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.
ZFX		-	-	GRCh38 GRCh37	33	187

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.
Intellectual developmental disorder, x-linked, syndromic 37	Pathogenic (1)	criteria provided, single submitter	Oct 28, 2024	RCV004771832.1

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.
Pathogenic (Oct 28, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Intellectual developmental disorder, x-linked, syndromic 37 (Autosomal dominant inheritance) Affected status: yes Allele origin: de novo	Institute for Genomic Medicine, Nationwide Children's Hospital Accession: SCV005382597.1 First in ClinVar: Nov 03, 2024 Last updated: Nov 03, 2024	Publications: PubMed (2) PubMed: 38325380‚ 32406922 Comment: The p.Met666Valfs2 variant was identified as a de novo mutation in an affected female proband (parentage confirmed). It is predicted to truncate the encoded protein … (more) The p.Met666Valfs2 variant was identified as a de novo mutation in an affected female proband (parentage confirmed). It is predicted to truncate the encoded protein by ~17% and would remove the key C-terminal DNA binding domains (Ni et al, 2020). Loss-of-function variants in ZFX are an established mechanism of disease and this specific change was observed in a previously published patient (Patient 13, Shepherdson et al, 2024). The p.Met666Valfs*2 variant is absent from large population databases of human genetic variation (gnomAD v4.1, RGC-ME, and All Of Us). We interpret it as a Pathogenic variant. (less) Number of individuals with the variant: 1 Clinical Features: Delayed gross motor development (present) , Delayed speech and language development (present) , Hypotonia (present) , Broad eyebrow (present) , Atypical behavior (present) , Intellectual … (more) Delayed gross motor development (present) , Delayed speech and language development (present) , Hypotonia (present) , Broad eyebrow (present) , Atypical behavior (present) , Intellectual disability, mild (present) , Smooth philtrum (present) , Macrocephaly (present) , Sensorineural hearing loss disorder (present) , Umbilical hernia (present) , Agenesis of cerebellar vermis (present) , Abnormal subclavian artery morphology (present) (less)

Comment:

The p.Met666Valfs*2 variant was identified as a de novo mutation in an affected female proband (parentage confirmed). It is predicted to truncate the encoded protein by ~17% and would remove the key C-terminal DNA binding domains (Ni et al, 2020). Loss-of-function variants in ZFX are an established mechanism of disease and this specific change was observed in a previously published patient (Patient 13, Shepherdson et al, 2024). The p.Met666Valfs*2 variant is absent from large population databases of human genetic variation (gnomAD v4.1, RGC-ME, and All Of Us). We interpret it as a Pathogenic 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
Variants in ZFX are associated with an X-linked neurodevelopmental disorder with recurrent facial gestalt.	Shepherdson JL	American journal of human genetics	2024	PMID: 38325380
Characterization of the ZFX family of transcription factors that bind downstream of the start site of CpG island promoters.	Ni W	Nucleic acids research	2020	PMID: 32406922

Text-mined citations for this variant ...

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_003410.4(ZFX):c.1996_1997del (p.Met666fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...