NM_003495.3(H4C9):c.122G>T (p.Arg41Leu) AND Tessadori-Van Haaften neurodevelopmental syndrome 4

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jan 20, 2023
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV003152473.8

Allele description [Variation Report for NM_003495.3(H4C9):c.122G>T (p.Arg41Leu)]

NM_003495.3(H4C9):c.122G>T (p.Arg41Leu)

Genes:

H2BC12:H2B clustered histone 12 [Gene - OMIM - HGNC]
H4C9:H4 clustered histone 9 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

6p22.1

Genomic location:

Preferred name:

NM_003495.3(H4C9):c.122G>T (p.Arg41Leu)

Other names:

H4C9, ARG41LEU

HGVS:

NC_000006.12:g.27139430G>T
NG_107574.1:g.293G>T
NG_107574.2:g.435G>T
NM_003495.3:c.122G>TMANE SELECT
NM_080593.2:c.*10-749C>A
NP_003486.1:p.Arg41Leu
NC_000006.11:g.27107209G>T
NM_003495.2:c.122G>T

Protein change:

R41L; ARG41LEU

Links:

OMIM: 602833.0001

Molecular consequence:

NM_080593.2:c.*10-749C>A - intron variant - [Sequence Ontology: SO:0001627]
NM_003495.3:c.122G>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Tessadori-Van Haaften neurodevelopmental syndrome 4 (TEBIVANED4)
Identifiers:: MONDO: MONDO:0031000; MedGen: C5677016; OMIM: 619951

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003841064	OMIM	no assertion criteria provided	Pathogenic (Jan 20, 2023)	germline	literature only	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003841064

OMIM

no assertion criteria provided

Pathogenic
(Jan 20, 2023)

germline

literature only

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

Recurrent de novo missense variants across multiple histone H4 genes underlie a neurodevelopmental syndrome.

Tessadori F, Duran K, Knapp K, Fellner M; Deciphering Developmental Disorders Study., Smithson S, Beleza Meireles A, Elting MW, Waisfisz Q, O'Donnell-Luria A, Nowak C, Douglas J, Ronan A, Brunet T, Kotzaeridou U, Svihovec S, Saenz MS, Thiffault I, Del Viso F, Devine P, Rego S, Tenney J, et al.

Am J Hum Genet. 2022 Apr 7;109(4):750-758. doi: 10.1016/j.ajhg.2022.02.003. Epub 2022 Feb 23.

PubMed [citation]

PMID:: 35202563
PMCID:: PMC9069069

Details of each submission

From OMIM, SCV003841064.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In a 10.5-year-old girl (P26) with Tessadori-Bicknell-van Haaften neurodevelopmental syndrome-4 (TEBIVANED4; 619951), Tessadori et al. (2022) identified a de novo heterozygous c.122G-T transversion (c.122G-T, NM_003495.2) in the H4C9 gene, resulting in an arg41-to-leu (R41L) 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 severe developmental defects, suggesting that it is pathogenic. The authors postulated a dominant effect. The patient had learning difficulties, social communication problems, poor growth with microcephaly (-4.12 SD), visual and hearing deficits, and dysmorphic facial features. The authors also referred to this mutation as ARG40LEU (R40L), reflecting the practice of dropping the numbering of the first posttranslationally removed methionine.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jun 9, 2024

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