NM_000127.3(EXT1):c.1536G>C (p.Gln512His) AND Multiple congenital exostosis

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Oct 31, 2019
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:: RCV001239646.7

Allele description [Variation Report for NM_000127.3(EXT1):c.1536G>C (p.Gln512His)]

NM_000127.3(EXT1):c.1536G>C (p.Gln512His)

Gene:

EXT1:exostosin glycosyltransferase 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

8q24.11

Genomic location:

Preferred name:

NM_000127.3(EXT1):c.1536G>C (p.Gln512His)

HGVS:

NC_000008.11:g.117819676C>G
NG_007455.2:g.297144G>C
NM_000127.3:c.1536G>CMANE SELECT
NP_000118.2:p.Gln512His
LRG_493t1:c.1536G>C
LRG_493:g.297144G>C
NC_000008.10:g.118831915C>G
NM_000127.2:c.1536G>C

Protein change:

Q512H

Links:

dbSNP: rs1811889486

NCBI 1000 Genomes Browser:

rs1811889486

Molecular consequence:

NM_000127.3:c.1536G>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Multiple congenital exostosis (EXT)
Synonyms:: MULTIPLE CARTILAGINOUS EXOSTOSES; Hereditary multiple osteochondromas; Multiple exostoses; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0005508; MedGen: C0015306; Orphanet: 321; OMIM: PS133700; Human Phenotype Ontology: HP:0002762

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001412535	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 31, 2019)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 17576681, 9536098, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001412535

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Oct 31, 2019)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization.

Buratti E, Chivers M, Královicová J, Romano M, Baralle M, Krainer AR, Vorechovsky I.

Nucleic Acids Res. 2007;35(13):4250-63. Epub 2007 Jun 18.

PubMed [citation]

PMID:: 17576681
PMCID:: PMC1934990

Statistical features of human exons and their flanking regions.

Zhang MQ.

Hum Mol Genet. 1998 May;7(5):919-32.

PubMed [citation]

PMID:: 9536098

See all PubMed Citations (3)

Details of each submission

From Invitae, SCV001412535.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with EXT1-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamine with histidine at codon 512 of the EXT1 protein (p.Gln512His). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and histidine. This variant also falls at the last nucleotide of exon 6 of the EXT1 coding sequence, which is part of the consensus splice site for this exon.

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

Last Updated: Mar 30, 2024

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