NM_002107.7(H3-3A):c.271G>C (p.Gly91Arg) AND Bryant-Li-Bhoj neurodevelopmental syndrome 1

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Apr 3, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV001823779.3

Allele description [Variation Report for NM_002107.7(H3-3A):c.271G>C (p.Gly91Arg)]

NM_002107.7(H3-3A):c.271G>C (p.Gly91Arg)

Gene:

H3-3A:H3.3 histone A [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1q42.12

Genomic location:

Preferred name:

NM_002107.7(H3-3A):c.271G>C (p.Gly91Arg)

Other names:

H3F3A, GLY91ARG

HGVS:

NC_000001.11:g.226065798G>C
NG_065173.1:g.8092G>C
NM_001379043.1:c.271G>C
NM_001379045.1:c.271G>C
NM_001379046.1:c.271G>C
NM_001379047.1:c.271G>C
NM_002107.7:c.271G>CMANE SELECT
NP_001365972.1:p.Gly91Arg
NP_001365974.1:p.Gly91Arg
NP_001365975.1:p.Gly91Arg
NP_001365976.1:p.Gly91Arg
NP_002098.1:p.Gly91Arg
LRG_1410t1:c.271G>C
LRG_1410:g.8092G>C
LRG_1410p1:p.Gly91Arg
NC_000001.10:g.226253499G>C
NM_002107.4:c.271G>C

Protein change:

G91R; GLY91ARG

Links:

OMIM: 601128.0003; dbSNP: rs2102737050

NCBI 1000 Genomes Browser:

rs2102737050

Molecular consequence:

NM_001379043.1:c.271G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001379045.1:c.271G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001379046.1:c.271G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001379047.1:c.271G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_002107.7:c.271G>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Bryant-Li-Bhoj neurodevelopmental syndrome 1 (BRYLIB1)
Identifiers:: MONDO: MONDO:0030606; MedGen: C5676905; OMIM: 619720

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002073378	OMIM	no assertion criteria provided	Pathogenic (Feb 1, 2022)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 33268356, 34876591
SCV003925629	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Apr 3, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002073378

OMIM

no assertion criteria provided

Pathogenic
(Feb 1, 2022)

germline

literature only

PubMed (2)
[See all records that cite these PMIDs]

SCV003925629

Institute of Human Genetics, University of Leipzig Medical Center

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Apr 3, 2023)

unknown

clinical testing

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
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Histone H3.3 beyond cancer: Germline mutations in Histone 3 Family 3A and 3B cause a previously unidentified neurodegenerative disorder in 46 patients.

Bryant L, Li D, Cox SG, Marchione D, Joiner EF, Wilson K, Janssen K, Lee P, March ME, Nair D, Sherr E, Fregeau B, Wierenga KJ, Wadley A, Mancini GMS, Powell-Hamilton N, van de Kamp J, Grebe T, Dean J, Ross A, Crawford HP, Powis Z, et al.

Sci Adv. 2020 Dec 2;6(49). doi:pii: eabc9207. 10.1126/sciadv.abc9207. Print 2020 Dec.

PubMed [citation]

PMID:: 33268356
PMCID:: PMC7821880

De novo variants in H3-3A and H3-3B are associated with neurodevelopmental delay, dysmorphic features, and structural brain abnormalities.

Okur V, Chen Z, Vossaert L, Peacock S, Rosenfeld J, Zhao L, Du H, Calamaro E, Gerard A, Zhao S, Kelsay J, Lahr A, Mighton C, Porter HM, Siemon A, Silver J, Svihovec S, Fong CT, Grant CL, Lerner-Ellis J, Manickam K, Madan-Khetarpal S, et al.

NPJ Genom Med. 2021 Dec 7;6(1):104. doi: 10.1038/s41525-021-00268-8.

PubMed [citation]

PMID:: 34876591
PMCID:: PMC8651650

See all PubMed Citations (3)

Details of each submission

From OMIM, SCV002073378.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (2)

Description

In an 8-year-old girl (patient 20) with Bryant-Li-Bhoj neurodevelopmental syndrome-1 (BRYLIB1; 619720), Bryant et al. (2020) identified a de novo heterozygous c.271G-C transversion (c.271G-C, NM_002107.4) in the H3F3A gene, resulting in a gly91-to-arg (G91R) substitution. The mutation, which was found by exome sequencing, was not present in the gnomAD database. The authors noted that this mutation would be described as GLY90ARG (G90R) according to standard histone nomenclature, which omits numbering the initiator methionine. Molecular modeling suggested that the mutation could disrupt chaperone binding. In vitro studies of pooled patient cells showed some evidence of dysregulated histone posttranslational modifications as well as enhanced proliferation. The patient had severe global developmental delay with inability to walk or speak. She also had progressive short stature, hypo/hypertonia, and dysmorphic facial features.

In a 28-year-old female (patient 2) with BRYLIB1, Okur et al. (2021) identified a de novo heterozygous G91R mutation in the H3F3A gene. The mutant protein localized normally to the nucleus and was expressed at normal levels. Molecular modeling suggested that the mutation would not have an effect on histone PTM. The patient had short stature, global developmental delay, microcephaly, hypotonia, hypertonia of the extremities, and seizures.

#	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

From Institute of Human Genetics, University of Leipzig Medical Center, SCV003925629.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

_x000D_ Criteria applied: PS4_MOD, PM2_SUP, PP2

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

Last Updated: Dec 24, 2023

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