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NM_000141.5(FGFR2):c.963C>A (p.Asp321Glu) AND FGFR2-related craniosynostosis

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Dec 27, 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:
RCV003831149.2

Allele description [Variation Report for NM_000141.5(FGFR2):c.963C>A (p.Asp321Glu)]

NM_000141.5(FGFR2):c.963C>A (p.Asp321Glu)

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.963C>A (p.Asp321Glu)
HGVS:
  • NC_000010.11:g.121517440G>T
  • NG_012449.2:g.86019C>A
  • NM_000141.5:c.963C>AMANE SELECT
  • NM_001144913.1:c.1087+1242C>A
  • NM_001144914.1:c.749-2121C>A
  • NM_001144915.2:c.696C>A
  • NM_001144916.2:c.618C>A
  • NM_001144917.2:c.939+2539C>A
  • NM_001144918.2:c.618C>A
  • NM_001144919.2:c.820+1242C>A
  • NM_001320654.2:c.279C>A
  • NM_001320658.2:c.963C>A
  • NM_022970.4:c.1087+1242C>A
  • NM_023029.2:c.696C>A
  • NP_000132.3:p.Asp321Glu
  • NP_000132.3:p.Asp321Glu
  • NP_001138387.1:p.Asp232Glu
  • NP_001138388.1:p.Asp206Glu
  • NP_001138390.1:p.Asp206Glu
  • NP_001307583.1:p.Asp93Glu
  • NP_001307587.1:p.Asp321Glu
  • NP_075418.1:p.Asp232Glu
  • LRG_994t1:c.963C>A
  • LRG_994:g.86019C>A
  • LRG_994p1:p.Asp321Glu
  • NC_000010.10:g.123276954G>T
  • NM_000141.4:c.963C>A
  • NR_073009.2:n.1399C>A
Protein change:
D206E
Molecular consequence:
  • NM_001144913.1:c.1087+1242C>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001144914.1:c.749-2121C>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001144917.2:c.939+2539C>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001144919.2:c.820+1242C>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_022970.4:c.1087+1242C>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000141.5:c.963C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001144915.2:c.696C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001144916.2:c.618C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001144918.2:c.618C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001320654.2:c.279C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001320658.2:c.963C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_023029.2:c.696C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NR_073009.2:n.1399C>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:
FGFR2-related craniosynostosis
Identifiers:
MedGen: CN231480

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV004637284Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Likely pathogenic
(Dec 27, 2023) 		germlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

FGFR2 mutations in Pfeiffer syndrome.

Lajeunie E, Ma HW, Bonaventure J, Munnich A, Le Merrer M, Renier D.

Nat Genet. 1995 Feb;9(2):108. No abstract available.

PubMed [citation]
PMID:
7719333

[A study of genetic heterogeneity in Pfeiffer syndrome].

Ma H, Wang Y, Mi Z, Hao M, Yang L, Zhao S, Ji S, Jing Z.

Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 1998 Apr 10;15(2):81-4. Chinese.

PubMed [citation]
PMID:
9531645
See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004637284.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)

Description

This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 321 of the FGFR2 protein (p.Asp321Glu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with FGFR2-related conditions. 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 with a positive predictive value of 95%. This variant disrupts the p.Asp321 amino acid residue in FGFR2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7719333, 9531645, 9586546, 10394936, 29109840; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024