VCV000427725.3 - ClinVar

NM_004773.4(ZNHIT3):c.92C>T (p.Ser31Leu)

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.

(3)

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.

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_004773.4(ZNHIT3):c.92C>T (p.Ser31Leu)

Variation ID: 427725 Accession: VCV000427725.3

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 17q12 17: 36486940 (GRCh38) [ NCBI UCSC ] 17: 34842784 (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	Jun 5, 2017	Nov 29, 2021	May 29, 2020

HGVS

Nucleotide	Protein	Molecular consequence
NM_004773.4(ZNHIT3):c.92C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		missense
NM_004773.4:c.92C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_004764.1:p.Ser31Leu	missense
NM_001281432.2:c.92C>T	NP_001268361.1:p.Ser31Leu	missense
NM_001281433.2:c.92C>T	NP_001268362.1:p.Ser31Leu	missense
NM_001281434.2:c.92C>T	NP_001268363.1:p.Ser31Leu	missense
NR_104009.2:n.111C>T		non-coding transcript variant
NC_000017.11:g.36486940C>T
NC_000017.10:g.34842784C>T

... more HGVS ... less HGVS

Protein change

S31L

Other names

ZNHIT3, SER31LEU (rs148890852)

Canonical SPDI

NC_000017.11:36486939: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.

0.00020 (T)

Allele frequency Help The frequency of the allele represented by this VCV record.

Trans-Omics for Precision Medicine (TOPMed) 0.00001

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008

1000 Genomes Project 30x 0.00016

1000 Genomes Project 0.00020

Exome Aggregation Consortium (ExAC) 0.00034

The Genome Aggregation Database (gnomAD), exomes 0.00042

The Genome Aggregation Database (gnomAD) 0.00044

Links

ClinGen: CA289920218 OMIM: 604500.0001 dbSNP: rs148890852 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.
ZNHIT3		-	-	GRCh38 GRCh38 GRCh37	25	156

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.
PEHO syndrome	Likely pathogenic (3)	criteria provided, multiple submitters, no conflicts	May 29, 2020	RCV000490627.4

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.
Likely pathogenic (May 29, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	PEHO syndrome (Autosomal recessive inheritance) Affected status: unknown Allele origin: germline	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard Accession: SCV001430796.1 First in ClinVar: Aug 23, 2020 Last updated: Aug 23, 2020	Publications: PubMed (2) PubMed: 31048081‚ 28335020 Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/80bf9ebd-06a5-497c-a9c7-bf5b46a4ae19 Comment: The heterozygous p.Ser31Leu variant in ZNHIT3 was identified by our study, in the compound heterozygous state, along with another likely pathogenic variant, in an individual … (more) The heterozygous p.Ser31Leu variant in ZNHIT3 was identified by our study, in the compound heterozygous state, along with another likely pathogenic variant, in an individual with PEHO syndrome (PMID: 31048081). This variant has also been reported in 22 additional individuals with PEHO syndrome, segregated with disease in 4 affected relatives from 2 families (PMID: 28335020), which increases the likelihood that the p.Ser31Leu variant is pathogenic. The variant has also been reported as pathogenic by OMIM in ClinVar (Variation ID: 427725). The p.Ser31Leu variant has been identified in 0.476% (119/25006) of European (Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs148890852). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. The p.Ser31Leu is located in a region of ZNHIT3 that is essential to protein folding and stability, suggesting that this variant is in a functional domain and slightly supports pathogenicity (PMID: 28335020). Additionally, animal models in zebrafish and in vitro functional studies have shown that this variant causes PEHO syndrome (PMID: 28335020). However, these types of experiments may not accurately represent biological function. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PS3, PM3, PM1_Supporting, PP1 (Richards 2015). (less)
Likely pathogenic (Apr 25, 2020)	criteria provided, single submitter (NYGC Assertion Criteria 2020) Method: clinical testing	PEHO syndrome Affected status: unknown Allele origin: germline	New York Genome Center Study: CSER-NYCKidSeq Accession: SCV002025627.1 First in ClinVar: Nov 29, 2021 Last updated: Nov 29, 2021	Clinical Features: Autistic behavior (present) , Seizure (present) , Intellectual disability (present) Secondary finding: no
Pathogenic (Jun 01, 2017)	no assertion criteria provided Method: literature only	PEHO SYNDROME Affected status: not provided Allele origin: germline	OMIM Accession: SCV000579317.1 First in ClinVar: Jun 05, 2017 Last updated: Jun 05, 2017	Publications: PubMed (1) PubMed: 28335020 Comment on evidence: In 24 patients of Finnish descent with PEHO syndrome (260565), Anttonen et al. (2017) identified a homozygous c.92C-T transition (c.92C-T, NM_004773.3) in the ZNHIT3 gene, … (more) In 24 patients of Finnish descent with PEHO syndrome (260565), Anttonen et al. (2017) identified a homozygous c.92C-T transition (c.92C-T, NM_004773.3) in the ZNHIT3 gene, resulting in a ser31-to-leu (S31L) substitution at a highly conserved residue in the zinc finger-HIT domain located next to one of the zinc-coordinating cysteines. The mutation in the first 3 patients was found by a combination of homozygosity mapping and Sanger sequencing of candidate genes; the mutation in 1 patient was found by whole-exome sequencing. The mutation segregated with the disorder in all families. It was found in heterozygous state at a low frequency in the ExAC database (0.07%), and at a slightly higher frequency (0.92%) among Finnish individuals. The mutant protein was unstable and underwent more rapid proteasomal degradation compared to wildtype. It also tended to form large nuclear aggregates, suggesting impaired folding with subsequent degradation. Injection of the S31L mutant was unable to rescue the microcephaly, cerebellar atrophy, and pericardiac edema of zebrafish embryos with morpholino knockdown of the znhit3 gene, suggesting that the mutation results in a loss of function. (less)

Comment:

The heterozygous p.Ser31Leu variant in ZNHIT3 was identified by our study, in the compound heterozygous state, along with another likely pathogenic variant, in an individual with PEHO syndrome (PMID: 31048081). This variant has also been reported in 22 additional individuals with PEHO syndrome, segregated with disease in 4 affected relatives from 2 families (PMID: 28335020), which increases the likelihood that the p.Ser31Leu variant is pathogenic. The variant has also been reported as pathogenic by OMIM in ClinVar (Variation ID: 427725). The p.Ser31Leu variant has been identified in 0.476% (119/25006) of European (Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs148890852). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. The p.Ser31Leu is located in a region of ZNHIT3 that is essential to protein folding and stability, suggesting that this variant is in a functional domain and slightly supports pathogenicity (PMID: 28335020). Additionally, animal models in zebrafish and in vitro functional studies have shown that this variant causes PEHO syndrome (PMID: 28335020). However, these types of experiments may not accurately represent biological function. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PS3, PM3, PM1_Supporting, PP1 (Richards 2015).

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
PEHO syndrome caused by compound heterozygote variants in ZNHIT3 gene.	Õunap K	European journal of medical genetics	2020	PMID: 31048081
ZNHIT3 is defective in PEHO syndrome, a severe encephalopathy with cerebellar granule neuron loss.	Anttonen AK	Brain : a journal of neurology	2017	PMID: 28335020
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/80bf9ebd-06a5-497c-a9c7-bf5b46a4ae19	-	-	-	-

Text-mined citations for rs148890852 ...

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 Mar 30, 2024

ClinVar Genomic variation as it relates to human health

NM_004773.4(ZNHIT3):c.92C>T (p.Ser31Leu)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs148890852 ...