NM_000141.5(FGFR2):c.1066T>G (p.Trp356Gly) AND FGFR2-related craniosynostosis

This record was updated by the submitter. Please see the current version.

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Mar 10, 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:: RCV003028849.2

Allele description

NM_000141.5(FGFR2):c.1066T>G (p.Trp356Gly)

Gene:

FGFR2:fibroblast growth factor receptor 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

10q26.13

Genomic location:

Preferred name:

NM_000141.5(FGFR2):c.1066T>G (p.Trp356Gly)

HGVS:

NC_000010.11:g.121517337A>C
NG_012449.2:g.86122T>G
NM_000141.5:c.1066T>GMANE SELECT
NM_001144913.1:c.1087+1345T>G
NM_001144914.1:c.749-2018T>G
NM_001144915.2:c.799T>G
NM_001144916.2:c.721T>G
NM_001144917.2:c.939+2642T>G
NM_001144918.2:c.721T>G
NM_001144919.2:c.820+1345T>G
NM_001320654.2:c.382T>G
NM_001320658.2:c.1066T>G
NM_022970.4:c.1087+1345T>G
NM_023029.2:c.799T>G
NP_000132.3:p.Trp356Gly
NP_000132.3:p.Trp356Gly
NP_001138387.1:p.Trp267Gly
NP_001138388.1:p.Trp241Gly
NP_001138390.1:p.Trp241Gly
NP_001307583.1:p.Trp128Gly
NP_001307587.1:p.Trp356Gly
NP_075418.1:p.Trp267Gly
LRG_994t1:c.1066T>G
LRG_994:g.86122T>G
LRG_994p1:p.Trp356Gly
NC_000010.10:g.123276851A>C
NM_000141.4:c.1066T>G
NR_073009.2:n.1502T>G

Protein change:

W128G

Molecular consequence:

NM_001144913.1:c.1087+1345T>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001144914.1:c.749-2018T>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001144917.2:c.939+2642T>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001144919.2:c.820+1345T>G - intron variant - [Sequence Ontology: SO:0001627]
NM_022970.4:c.1087+1345T>G - intron variant - [Sequence Ontology: SO:0001627]
NM_000141.5:c.1066T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001144915.2:c.799T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001144916.2:c.721T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001144918.2:c.721T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001320654.2:c.382T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001320658.2:c.1066T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_023029.2:c.799T>G - missense variant - [Sequence Ontology: SO:0001583]
NR_073009.2:n.1502T>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: FGFR2-related craniosynostosis
Identifiers:: MedGen: CN231480

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003318681	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Mar 10, 2023)	germline	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

SCV003318681

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Mar 10, 2023)

germline

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

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Invitae, SCV003318681.2

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

Description

This sequence change replaces tryptophan, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 356 of the FGFR2 protein (p.Trp356Gly). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FGFR2 protein function. ClinVar contains an entry for this variant (Variation ID: 2103395). This missense change has been observed in individual(s) with FGFR2 related conditions (Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency).

#	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: Jul 23, 2024

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