VCV000809888.35 - ClinVar

NM_003545.4(H4C5):c.136C>T (p.Arg46Cys)

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.

(8)

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.

Conflicting classifications of pathogenicity
Pathogenic(1); Likely pathogenic(1); Uncertain significance(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_003545.4(H4C5):c.136C>T (p.Arg46Cys)

Variation ID: 809888 Accession: VCV000809888.35

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 6p22.2 6: 26204780 (GRCh38) [ NCBI UCSC ] 6: 26205008 (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 3, 2020	Oct 20, 2024	Jul 13, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_003545.4:c.136C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_003536.1:p.Arg46Cys	missense
NC_000006.12:g.26204780C>T
NC_000006.11:g.26205008C>T

Protein change

R46C

Other names

H4C5, ARG46CYS
p.R46C

Canonical SPDI

NC_000006.12:26204779: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

OMIM: 602830.0004 dbSNP: rs950721550 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.
H4C5		-	-	GRCh38 GRCh37	12	39
LOC129996027	-	-	-	GRCh38	-	15

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 (4)	criteria provided, single submitter	Sep 1, 2018	RCV000998549.24
See cases	Likely pathogenic (1)	criteria provided, single submitter	Apr 26, 2021	RCV001420269.3
Tessadori-Van Haaften neurodevelopmental syndrome 3	Pathogenic (2)	no assertion criteria provided	Feb 21, 2024	RCV003152614.3
not specified	Pathogenic (1)	criteria provided, single submitter	Jul 13, 2023	RCV004030242.1

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.
Likely pathogenic (Apr 26, 2021)	criteria provided, single submitter (Parc Tauli Hospital Assertion Criteria 2021) Method: clinical testing	See cases (Autosomal dominant inheritance) Affected status: yes Allele origin: de novo	Genetics Laboratory, UDIAT-Centre Diagnòstic, Hospital Universitari Parc Tauli Accession: SCV001622689.1 First in ClinVar: May 20, 2021 Last updated: May 20, 2021	Comment: PM2_supporting;PM6_moderate;PP3_supporting;PP5_supporting;BP1_supporting Clinical Features: Global developmental delay (present) , Intellectual disability (present) , Motor stereotypies (present) , Bruxism (present) , Delayed speech and language development (present) Sex: female
Pathogenic (Jul 13, 2023)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV004067378.2 First in ClinVar: Oct 28, 2023 Last updated: May 01, 2024	Publications: PubMed (1) PubMed: 35202563 Comment: The c.136C>T (p.R46C) alteration is located in exon 1 (coding exon 1) of the HIST1H4E gene. This alteration results from a C to T substitution … (more) The c.136C>T (p.R46C) alteration is located in exon 1 (coding exon 1) of the HIST1H4E gene. This alteration results from a C to T substitution at nucleotide position 136, causing the arginine (R) at amino acid position 46 to be replaced by a cysteine (C). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been determined to be the result of a de novo mutation in multiple individuals with features consistent with H4C5-related Tessadori-van Haaften neurodevelopmental syndrome (Tessadori, 2022). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. (less)
Uncertain significance (Sep 01, 2018)	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: SCV001154679.27 First in ClinVar: Feb 03, 2020 Last updated: Oct 20, 2024	Number of individuals with the variant: 1
Uncertain significance (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) Study: VKGL Data-share Consensus Accession: SCV001798535.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021
Uncertain significance (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, Amsterdam University Medical Center Study: VKGL Data-share Consensus Accession: SCV001808124.1 First in ClinVar: Aug 25, 2021 Last updated: Aug 25, 2021
Uncertain significance (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001968407.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021
Pathogenic (Jan 20, 2023)	no assertion criteria provided Method: literature only	TESSADORI-BICKNELL-VAN HAAFTEN NEURODEVELOPMENTAL SYNDROME 3 Affected status: not provided Allele origin: germline	OMIM Accession: SCV003841062.1 First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023	Publications: PubMed (1) PubMed: 35202563 Comment on evidence: In 7 unrelated patients (P16-P22) with Tessadori-Bicknell-van Haaften neurodevelopmental syndrome-3 (TEBIVANED3; 619950), Tessadori et al. (2022) identified a de novo heterozygous c.136C-T transition (c.136C-T, NM_003545.3) … (more) In 7 unrelated patients (P16-P22) with Tessadori-Bicknell-van Haaften neurodevelopmental syndrome-3 (TEBIVANED3; 619950), Tessadori et al. (2022) identified a de novo heterozygous c.136C-T transition (c.136C-T, NM_003545.3) in the H4C5 gene, resulting in an arg46-to-cys (R46C) substitution at a conserved residue in the core globular domain. The mutation, which was found by exome sequencing, was not present in the gnomAD database. Expression of the mutation in zebrafish embryos induced mild developmental defects that just reached significance (p less that 0.05), suggesting that it may be pathogenic. The authors postulated a dominant effect. The patients had poor overall growth and global developmental delay, but there was phenotypic heterogeneity. The authors also referred to this mutation as ARG45CYS (R45C), reflecting the practice of dropping the numbering of the first posttranslationally removed methionine. (less)
Pathogenic (Feb 21, 2024)	no assertion criteria provided Method: clinical testing	Tessadori-Van Haaften neurodevelopmental syndrome 3 Affected status: yes Allele origin: de novo	Undiagnosed Diseases Network, NIH Study: Undiagnosed Diseases Network (NIH), UDN Accession: SCV005368744.1 First in ClinVar: Oct 13, 2024 Last updated: Oct 13, 2024	Comment: matches phenotype, RNASeq confirms pathogenicity Number of individuals with the variant: 1 Clinical Features: Chordee (present) , Small for gestational age (present) , Poor suck (present) , Hypothermia (present) , Premature birth following premature rupture of fetal membranes (present) … (more) Chordee (present) , Small for gestational age (present) , Poor suck (present) , Hypothermia (present) , Premature birth following premature rupture of fetal membranes (present) , Erythema (present) , Dilatation of the renal pelvis (present) , Nuchal cord (present) , Urinary incontinence (present) , Progressive microcephaly (present) , Anteverted nares (present) , Astigmatism (present) , Myopia (present) , Exotropia (present) , Nasolacrimal duct obstruction (present) , Delayed speech and language development (present) , Cerebellar ataxia (present) , Absent speech (present) , Umbilical hernia (present) , Diastasis recti (present) , Pes planus (present) , Gastroesophageal reflux (present) , Delayed CNS myelination (present) , Delayed gross motor development (present) , Abnormal cerebral white matter morphology (present) , Bowel incontinence (present) , Generalized joint hypermobility (present) , Elevated circulating creatine kinase concentration (present) , Butterfly vertebrae (present) , Steppage gait (present) , Pelvic girdle muscle weakness (present) , Short stature (present) , Delayed brainstem auditory evoked response conduction time (present) , Widely-spaced incisors (present) , Cerebral hypomyelination (present) , Few cafe-au-lait spots (present) , Postnatal growth retardation (present) , Prominent crus of helix (present) , Bilateral coxa valga (present) , Delayed fine motor development (present) , Moderate expressive language delay (present) , Moderate receptive language delay (present) , Decreased circulating ferritin concentration (present) , Decreased transferrin saturation (present) , Elevated brain choline level by MRS (present) , Wide nasal base (present) , Decreased circulating vitamin D concentration (present) (less) Age: 10-19 years Sex: male Tissue: Blood

Comment:

The c.136C>T (p.R46C) alteration is located in exon 1 (coding exon 1) of the HIST1H4E gene. This alteration results from a C to T substitution at nucleotide position 136, causing the arginine (R) at amino acid position 46 to be replaced by a cysteine (C). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been determined to be the result of a de novo mutation in multiple individuals with features consistent with H4C5-related Tessadori-van Haaften neurodevelopmental syndrome (Tessadori, 2022). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified 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
Recurrent de novo missense variants across multiple histone H4 genes underlie a neurodevelopmental syndrome.	Tessadori F	American journal of human genetics	2022	PMID: 35202563

Text-mined citations for rs950721550 ...

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 Nov 03, 2024

ClinVar Genomic variation as it relates to human health

NM_003545.4(H4C5):c.136C>T (p.Arg46Cys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs950721550 ...