NM_000142.5(FGFR3):c.1619A>C (p.Asn540Thr) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Dec 11, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV001549822.13

Allele description [Variation Report for NM_000142.5(FGFR3):c.1619A>C (p.Asn540Thr)]

NM_000142.5(FGFR3):c.1619A>C (p.Asn540Thr)

Gene:

FGFR3:fibroblast growth factor receptor 3 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

4p16.3

Genomic location:

Preferred name:

NM_000142.5(FGFR3):c.1619A>C (p.Asn540Thr)

HGVS:

NC_000004.12:g.1805643A>C
NG_012632.1:g.17332A>C
NM_000142.5:c.1619A>CMANE SELECT
NM_001163213.2:c.1625A>C
NM_001354809.2:c.1622A>C
NM_001354810.2:c.1622A>C
NM_022965.4:c.1283A>C
NP_000133.1:p.Asn540Thr
NP_000133.1:p.Asn540Thr
NP_001156685.1:p.Asn542Thr
NP_001341738.1:p.Asn541Thr
NP_001341739.1:p.Asn541Thr
NP_075254.1:p.Asn428Thr
LRG_1021t1:c.1619A>C
LRG_1021:g.17332A>C
LRG_1021p1:p.Asn540Thr
NC_000004.11:g.1807370A>C
NM_000142.4:c.1619A>C
NR_148971.2:n.2045A>C
P22607:p.Asn540Thr

Protein change:

N428T; ASN540THR

Links:

UniProtKB: P22607#VAR_004159; OMIM: 134934.0018; dbSNP: rs77722678

NCBI 1000 Genomes Browser:

rs77722678

Molecular consequence:

NM_000142.5:c.1619A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001163213.2:c.1625A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354809.2:c.1622A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354810.2:c.1622A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_022965.4:c.1283A>C - missense variant - [Sequence Ontology: SO:0001583]
NR_148971.2:n.2045A>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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LOC132183270 [Corylus avellana]
LOC132183270 [Corylus avellana]
Gene ID:132183270

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001770044	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Dec 11, 2023)	germline	clinical testing	Citation Link,
SCV002037525	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV002037932	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV002507644	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jun 3, 2020)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 7670477, 8589686, 25614871, 9452043, 28492532

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Summary from all submissions

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

Citations

PubMed

A recurrent mutation in the tyrosine kinase domain of fibroblast growth factor receptor 3 causes hypochondroplasia.

Bellus GA, McIntosh I, Smith EA, Aylsworth AS, Kaitila I, Horton WA, Greenhaw GA, Hecht JT, Francomano CA.

Nat Genet. 1995 Jul;10(3):357-9.

PubMed [citation]

PMID:: 7670477

A common FGFR3 gene mutation in hypochondroplasia.

Prinos P, Costa T, Sommer A, Kilpatrick MW, Tsipouras P.

Hum Mol Genet. 1995 Nov;4(11):2097-101.

PubMed [citation]

PMID:: 8589686

See all PubMed Citations (5)

Details of each submission

From GeneDx, SCV001770044.4

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

Description

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25728633, 9452043, 30048571, 30681580, 35438268)

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

From Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus, SCV002037525.1

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

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

From Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus, SCV002037932.1

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

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002507644.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

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. This variant disrupts the p.Asn540 amino acid residue in FGFR3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7670477, 8589686, 9452043, 25614871). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has been observed in individual(s) with clinical features of autosomal dominant hypochondroplasia (PMID: 9452043, Invitae). It has also been observed to segregate with disease in related individuals. This variant is also known as c.1658A>C in the literature. ClinVar contains an entry for this variant (Variation ID: 16344). This variant is not present in population databases (ExAC no frequency). This sequence change replaces asparagine with threonine at codon 540 of the FGFR3 protein (p.Asn540Thr). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and threonine.

#	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: Oct 26, 2024

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