VCV000453188.6 - ClinVar

NM_022095.4(ZNF335):c.3998A>G (p.Glu1333Gly)

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.

(5)

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.

Uncertain significance

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_022095.4(ZNF335):c.3998A>G (p.Glu1333Gly)

Variation ID: 453188 Accession: VCV000453188.6

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 20q13.12 20: 45948984 (GRCh38) [ NCBI UCSC ] 20: 44577623 (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	Dec 19, 2017	Dec 31, 2022	Mar 2, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_022095.4:c.3998A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_071378.1:p.Glu1333Gly	missense
NC_000020.11:g.45948984T>C
NC_000020.10:g.44577623T>C
NG_029772.1:g.28211A>G

Protein change

E1333G

Other names

Canonical SPDI

NC_000020.11:45948983:T:C

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.

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008

The Genome Aggregation Database (gnomAD), exomes 0.00010

Trans-Omics for Precision Medicine (TOPMed) 0.00025

Trans-Omics for Precision Medicine (TOPMed) 0.00019

Exome Aggregation Consortium (ExAC) 0.00009

The Genome Aggregation Database (gnomAD) 0.00025

The Genome Aggregation Database (gnomAD) 0.00022

Links

ClinGen: CA9884741 OMIM: 610827.0005 dbSNP: rs200635860 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.
ZNF335		-	-	GRCh38 GRCh37	575	587

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.
not provided	Uncertain significance (1)	criteria provided, single submitter	May 30, 2018	RCV000520219.2
Microcephalic primordial dwarfism due to ZNF335 deficiency	Uncertain significance (4)	criteria provided, multiple submitters, no conflicts	Mar 2, 2022	RCV000709924.5

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.
Uncertain significance (May 30, 2018)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000622062.2 First in ClinVar: Dec 19, 2017 Last updated: Apr 17, 2019	Comment: The E1333G variant in the ZNF335 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. While … (more) The E1333G variant in the ZNF335 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. While not seen in the homozygous state, the E1333G variant is observed in 27/126596 (0.02%) alleles in large population cohorts (Lek et al., 2016). The E1333G variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret E1333G as a variant of uncertain significance. (less)
Uncertain significance (May 06, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Microcephalic primordial dwarfism due to ZNF335 deficiency (Autosomal recessive inheritance) Affected status: unknown Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV002768907.1 First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022	Publications: PubMed (1) PubMed: 29652087 Comment: Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. 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 VUS-3B. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with primary microcephaly 10 (MIM#615095). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to glycine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 for a recessive condition (36 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (9 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been reported as VUS in a patient with microcephaly (ClinVar, PMID: 29652087). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
Uncertain significance (Mar 02, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Microcephalic primordial dwarfism due to ZNF335 deficiency Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002788875.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Pathogenic (Feb 19, 2019)	no assertion criteria provided Method: literature only	MICROCEPHALY 10, PRIMARY, AUTOSOMAL RECESSIVE Affected status: not provided Allele origin: germline	OMIM Accession: SCV000886425.1 First in ClinVar: Feb 25, 2019 Last updated: Feb 25, 2019	Publications: PubMed (1) PubMed: 29652087 Comment on evidence: For discussion of the c.3998A-G transition (c.3998A-G, NM_022095.3) in the ZNF335 gene, predicted to result in a glu1333-to-gly (E1333G) substitution, that was found in compound … (more) For discussion of the c.3998A-G transition (c.3998A-G, NM_022095.3) in the ZNF335 gene, predicted to result in a glu1333-to-gly (E1333G) substitution, that was found in compound heterozygous state in a patient with autosomal recessive primary microcephaly-10 (MCPH10; 615095) by Stouffs et al. (2018), see 610827.0004. (less)
not provided (-)	no classification provided Method: phenotyping only	Microcephalic primordial dwarfism due to ZNF335 deficiency Affected status: unknown Allele origin: maternal	GenomeConnect, ClinGen Accession: SCV000840269.1 First in ClinVar: Oct 14, 2018 Last updated: Oct 14, 2018	Comment: 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 … (more) 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: Failure to thrive (present) , Abnormality of the skull (present) , Abnormal facial shape (present) , Abnormality of eye movement (present) , Seizures (present) , … (more) Failure to thrive (present) , Abnormality of the skull (present) , Abnormal facial shape (present) , Abnormality of eye movement (present) , Seizures (present) , Hypertonia (present) , Abnormality of coordination (present) , Morphological abnormality of the central nervous system (present) , Abnormality of muscle physiology (present) , Abnormality of the stomach (present) , Abnormality of esophagus morphology (present) , Feeding difficulties (present) (less) Indication for testing: Diagnostic Age: 0-9 years Sex: male Method: Sanger Sequencing Testing laboratory: GeneDx Date variant was reported to submitter: 2017-11-03 Testing laboratory interpretation: Uncertain significance

Comment:

The E1333G variant in the ZNF335 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. While not seen in the homozygous state, the E1333G variant is observed in 27/126596 (0.02%) alleles in large population cohorts (Lek et al., 2016). The E1333G variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret E1333G as a variant of uncertain significance.

Comment:

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with primary microcephaly 10 (MIM#615095). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to glycine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 for a recessive condition (36 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (9 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been reported as VUS in a patient with microcephaly (ClinVar, PMID: 29652087). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) 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

Title	Author	Journal	Year	Link
Expanding the clinical spectrum of biallelic ZNF335 variants.	Stouffs K	Clinical genetics	2018	PMID: 29652087

Text-mined citations for rs200635860 ...

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 Jan 07, 2023

ClinVar Genomic variation as it relates to human health

NM_022095.4(ZNF335):c.3998A>G (p.Glu1333Gly)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs200635860 ...