VCV000013266.28 - ClinVar

NM_000141.5(FGFR2):c.1024T>C (p.Cys342Arg)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(12)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000141.5(FGFR2):c.1024T>C (p.Cys342Arg)

Variation ID: 13266 Accession: VCV000013266.28

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 10q26.13 10: 121517379 (GRCh38) [ NCBI UCSC ] 10: 123276893 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Apr 4, 2013	Mar 16, 2024	Jan 18, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000141.5:c.1024T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000132.3:p.Cys342Arg	missense
NM_022970.4:c.1087+1303T>C MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		intron variant
NM_001144913.1:c.1087+1303T>C		intron variant
NM_001144914.1:c.749-2060T>C		intron variant
NM_001144915.2:c.757T>C	NP_001138387.1:p.Cys253Arg	missense
NM_001144916.2:c.679T>C	NP_001138388.1:p.Cys227Arg	missense
NM_001144917.2:c.939+2600T>C		intron variant
NM_001144918.2:c.679T>C	NP_001138390.1:p.Cys227Arg	missense
NM_001144919.2:c.820+1303T>C		intron variant
NM_001320654.2:c.340T>C	NP_001307583.1:p.Cys114Arg	missense
NM_001320658.2:c.1024T>C	NP_001307587.1:p.Cys342Arg	missense
NM_023029.2:c.757T>C	NP_075418.1:p.Cys253Arg	missense
NR_073009.2:n.1460T>C		non-coding transcript variant
NC_000010.11:g.121517379A>G
NC_000010.10:g.123276893A>G
NG_012449.2:g.86080T>C
LRG_994:g.86080T>C
LRG_994t1:c.1024T>C	LRG_994p1:p.Cys342Arg
	P21802:p.Cys342Arg

... more HGVS ... less HGVS

Protein change

C342R, C114R, C253R, C227R

Other names

Canonical SPDI

NC_000010.11:121517378:A:G

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA256745 UniProtKB: P21802#VAR_004137 OMIM: 176943.0002 dbSNP: rs121918488 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
FGFR2		-	-	GRCh38 GRCh37	767	821

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Crouzon syndrome	Pathogenic (1)	no assertion criteria provided	Jan 1, 2000	RCV000014177.24
Jackson-Weiss syndrome	Pathogenic (1)	no assertion criteria provided	Jan 1, 2000	RCV000014179.24
Pfeiffer syndrome	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Aug 27, 2019	RCV000014178.28
Antley-Bixler syndrome without genital anomalies or disordered steroidogenesis	Pathogenic (2)	criteria provided, single submitter	-	RCV000014180.26
FGFR2-related craniosynostosis	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Jan 18, 2024	RCV000534888.12
not provided	Pathogenic (3)	criteria provided, single submitter	Feb 2, 2022	RCV001723565.6

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Aug 27, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Pfeiffer syndrome Affected status: unknown Allele origin: germline	Johns Hopkins Genomics, Johns Hopkins University Accession: SCV000998474.1 First in ClinVar: Nov 02, 2019 Last updated: Nov 02, 2019	Comment: This previously reported FGFR2 variant (rs121918488) is absent from large population datasets. Two submitters in ClinVar classify this variant as pathogenic. Multiple different missense changes … (more) This previously reported FGFR2 variant (rs121918488) is absent from large population datasets. Two submitters in ClinVar classify this variant as pathogenic. Multiple different missense changes have been reported in the same residue that have been shown to affect protein functionality. Two bioinformatic tools queried predict that the substitution would be possibly damaging, but these algorithms have low specificity, especially for predicting gain of function variants. This variant is considered pathogenic. (less)
Pathogenic (Sep 17, 2016)	criteria provided, single submitter (DGD Variant Analysis Guidelines) Method: clinical testing	Pfeiffer syndrome Affected status: yes Allele origin: germline	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia Accession: SCV000328390.2 First in ClinVar: Oct 11, 2015 Last updated: Mar 04, 2023 Comment: Clinical Testing	Number of individuals with the variant: 10
Pathogenic (Feb 02, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV002073983.2 First in ClinVar: Feb 11, 2022 Last updated: Mar 04, 2023	Comment: Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This … (more) Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 23754559, 9385368, 28901406, 8528214, 25759925, 7987400, 7719345, 25517871, 11343324, 8755573, 16418739, 11173845, 31837199, 12884424, 27228464, 24127277, 28600064, 29436723, 10633130, 10712195, 24656465, 10394936, 24411056, 27596331) (less)
Pathogenic (Jul 01, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	FGFR2-related craniosynostosis Affected status: yes Allele origin: germline	Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand Accession: SCV004034124.1 First in ClinVar: Sep 16, 2023 Last updated: Sep 16, 2023
Pathogenic (Jan 18, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	FGFR2-related craniosynostosis Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000659602.6 First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024	Publications: PubMed (4) PubMed: 7987400‚ 12884424‚ 24127277‚ 25759925 Comment: This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 342 of the FGFR2 protein … (more) This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 342 of the FGFR2 protein (p.Cys342Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Crouzon or Pfeiffer syndromes (PMID: 7987400, 12884424, 24127277, 25759925). ClinVar contains an entry for this variant (Variation ID: 13266). 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.Cys342 amino acid residue in FGFR2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24127277). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Antley-Bixler syndrome without genital anomalies or disordered steroidogenesis (Autosomal dominant inheritance) Affected status: yes Allele origin: de novo	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India Accession: SCV004800834.1 First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024	Sex: female
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001954661.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
Pathogenic (Jan 01, 2000)	no assertion criteria provided Method: literature only	CROUZON SYNDROME Affected status: not provided Allele origin: germline	OMIM Accession: SCV000034425.1 First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013	Publications: PubMed (4) PubMed: 7987400‚ 7719345‚ 8528214‚ 10633130 Comment on evidence: In a sporadic case of Crouzon syndrome (123500), Reardon et al. (1994) found a T-to-C transition at nucleotide 1036 predicted to result in a cys342-to-arg … (more) In a sporadic case of Crouzon syndrome (123500), Reardon et al. (1994) found a T-to-C transition at nucleotide 1036 predicted to result in a cys342-to-arg (C342R) substitution in the FGFR2 protein. The mutation created a new restriction site which was not found in the clinically normal parents of this patient. The same mutation was found in 5 patients with Pfeiffer syndrome (101600), not Crouzon syndrome, by Rutland et al. (1995). As a possible explanation, they pointed to the occurrence of 2 different phenotypes from the asp178-to-asn substitution in the prion protein gene, depending on the amino acid present at position 129 in the product of the same allele. The same mutation was found by Park et al. (1995) in a sporadic case of Jackson-Weiss syndrome (123150). The patient showed corneal synostosis, hypertelorism with ocular proptosis, midface hypoplasia, deviated nasal septum, obligatory mouthbreathing, moderate hearing deficit with hypoplastic ear canals, wide great toes with medial deviation, and tarsal-metatarsal coalescence (calcaneocuboidal fusions and right fusion of the navicular and first cuneiform bones). No hand anomalies were present by clinical or radiographic examination. In a patient with Antley-Bixler syndrome (ABS2; 207410), Reardon et al. (2000) identified the C342R substitution in the FGFR2 gene. The patient had normal male genitalia and a normal steroid profile. (less)
Pathogenic (Jan 01, 2000)	no assertion criteria provided Method: literature only	PFEIFFER SYNDROME Affected status: not provided Allele origin: germline	OMIM Accession: SCV000034426.1 First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013	Publications: PubMed (4) PubMed: 7987400‚ 7719345‚ 8528214‚ 10633130 Comment on evidence: In a sporadic case of Crouzon syndrome (123500), Reardon et al. (1994) found a T-to-C transition at nucleotide 1036 predicted to result in a cys342-to-arg … (more) In a sporadic case of Crouzon syndrome (123500), Reardon et al. (1994) found a T-to-C transition at nucleotide 1036 predicted to result in a cys342-to-arg (C342R) substitution in the FGFR2 protein. The mutation created a new restriction site which was not found in the clinically normal parents of this patient. The same mutation was found in 5 patients with Pfeiffer syndrome (101600), not Crouzon syndrome, by Rutland et al. (1995). As a possible explanation, they pointed to the occurrence of 2 different phenotypes from the asp178-to-asn substitution in the prion protein gene, depending on the amino acid present at position 129 in the product of the same allele. The same mutation was found by Park et al. (1995) in a sporadic case of Jackson-Weiss syndrome (123150). The patient showed corneal synostosis, hypertelorism with ocular proptosis, midface hypoplasia, deviated nasal septum, obligatory mouthbreathing, moderate hearing deficit with hypoplastic ear canals, wide great toes with medial deviation, and tarsal-metatarsal coalescence (calcaneocuboidal fusions and right fusion of the navicular and first cuneiform bones). No hand anomalies were present by clinical or radiographic examination. In a patient with Antley-Bixler syndrome (ABS2; 207410), Reardon et al. (2000) identified the C342R substitution in the FGFR2 gene. The patient had normal male genitalia and a normal steroid profile. (less)
Pathogenic (Jan 01, 2000)	no assertion criteria provided Method: literature only	JACKSON-WEISS SYNDROME Affected status: not provided Allele origin: germline	OMIM Accession: SCV000034427.1 First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013	Publications: PubMed (4) PubMed: 7987400‚ 7719345‚ 8528214‚ 10633130 Comment on evidence: In a sporadic case of Crouzon syndrome (123500), Reardon et al. (1994) found a T-to-C transition at nucleotide 1036 predicted to result in a cys342-to-arg … (more) In a sporadic case of Crouzon syndrome (123500), Reardon et al. (1994) found a T-to-C transition at nucleotide 1036 predicted to result in a cys342-to-arg (C342R) substitution in the FGFR2 protein. The mutation created a new restriction site which was not found in the clinically normal parents of this patient. The same mutation was found in 5 patients with Pfeiffer syndrome (101600), not Crouzon syndrome, by Rutland et al. (1995). As a possible explanation, they pointed to the occurrence of 2 different phenotypes from the asp178-to-asn substitution in the prion protein gene, depending on the amino acid present at position 129 in the product of the same allele. The same mutation was found by Park et al. (1995) in a sporadic case of Jackson-Weiss syndrome (123150). The patient showed corneal synostosis, hypertelorism with ocular proptosis, midface hypoplasia, deviated nasal septum, obligatory mouthbreathing, moderate hearing deficit with hypoplastic ear canals, wide great toes with medial deviation, and tarsal-metatarsal coalescence (calcaneocuboidal fusions and right fusion of the navicular and first cuneiform bones). No hand anomalies were present by clinical or radiographic examination. In a patient with Antley-Bixler syndrome (ABS2; 207410), Reardon et al. (2000) identified the C342R substitution in the FGFR2 gene. The patient had normal male genitalia and a normal steroid profile. (less)
Pathogenic (Jan 01, 2000)	no assertion criteria provided Method: literature only	ANTLEY-BIXLER SYNDROME WITHOUT GENITAL ANOMALIES OR DISORDERED STEROIDOGENESIS Affected status: not provided Allele origin: germline	OMIM Accession: SCV000034428.1 First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013	Publications: PubMed (4) PubMed: 7987400‚ 7719345‚ 8528214‚ 10633130 Comment on evidence: In a sporadic case of Crouzon syndrome (123500), Reardon et al. (1994) found a T-to-C transition at nucleotide 1036 predicted to result in a cys342-to-arg … (more) In a sporadic case of Crouzon syndrome (123500), Reardon et al. (1994) found a T-to-C transition at nucleotide 1036 predicted to result in a cys342-to-arg (C342R) substitution in the FGFR2 protein. The mutation created a new restriction site which was not found in the clinically normal parents of this patient. The same mutation was found in 5 patients with Pfeiffer syndrome (101600), not Crouzon syndrome, by Rutland et al. (1995). As a possible explanation, they pointed to the occurrence of 2 different phenotypes from the asp178-to-asn substitution in the prion protein gene, depending on the amino acid present at position 129 in the product of the same allele. The same mutation was found by Park et al. (1995) in a sporadic case of Jackson-Weiss syndrome (123150). The patient showed corneal synostosis, hypertelorism with ocular proptosis, midface hypoplasia, deviated nasal septum, obligatory mouthbreathing, moderate hearing deficit with hypoplastic ear canals, wide great toes with medial deviation, and tarsal-metatarsal coalescence (calcaneocuboidal fusions and right fusion of the navicular and first cuneiform bones). No hand anomalies were present by clinical or radiographic examination. In a patient with Antley-Bixler syndrome (ABS2; 207410), Reardon et al. (2000) identified the C342R substitution in the FGFR2 gene. The patient had normal male genitalia and a normal steroid profile. (less)
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001968516.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021
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Comment:

This previously reported FGFR2 variant (rs121918488) is absent from large population datasets. Two submitters in ClinVar classify this variant as pathogenic. Multiple different missense changes have been reported in the same residue that have been shown to affect protein functionality. Two bioinformatic tools queried predict that the substitution would be possibly damaging, but these algorithms have low specificity, especially for predicting gain of function variants. This variant is considered pathogenic.

Comment:

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 23754559, 9385368, 28901406, 8528214, 25759925, 7987400, 7719345, 25517871, 11343324, 8755573, 16418739, 11173845, 31837199, 12884424, 27228464, 24127277, 28600064, 29436723, 10633130, 10712195, 24656465, 10394936, 24411056, 27596331)

Comment:

This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 342 of the FGFR2 protein (p.Cys342Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Crouzon or Pfeiffer syndromes (PMID: 7987400, 12884424, 24127277, 25759925). ClinVar contains an entry for this variant (Variation ID: 13266). 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.Cys342 amino acid residue in FGFR2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24127277). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
The C342R mutation in FGFR2 causes Crouzon syndrome with elbow deformity.	Ke R	The Journal of craniofacial surgery	2015	PMID: 25759925
Genotype and clinical care correlations in craniosynostosis: findings from a cohort of 630 Australian and New Zealand patients.	Roscioli T	American journal of medical genetics. Part C, Seminars in medical genetics	2013	PMID: 24127277
Screening of patients with craniosynostosis: molecular strategy.	Chun K	American journal of medical genetics. Part A	2003	PMID: 12884424
Evidence for digenic inheritance in some cases of Antley-Bixler syndrome?	Reardon W	Journal of medical genetics	2000	PMID: 10633130
Novel FGFR2 mutations in Crouzon and Jackson-Weiss syndromes show allelic heterogeneity and phenotypic variability.	Park WJ	Human molecular genetics	1995	PMID: 8528214
Identical mutations in the FGFR2 gene cause both Pfeiffer and Crouzon syndrome phenotypes.	Rutland P	Nature genetics	1995	PMID: 7719345
Mutations in the fibroblast growth factor receptor 2 gene cause Crouzon syndrome.	Reardon W	Nature genetics	1994	PMID: 7987400

Text-mined citations for rs121918488 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000141.5(FGFR2):c.1024T>C (p.Cys342Arg)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs121918488 ...