NM_000142.5(FGFR3):c.1612A>G (p.Ile538Val) AND not provided

Germline classification:: Conflicting classifications of pathogenicity (3 submissions)
Last evaluated:: May 12, 2024
Review status:: criteria provided, conflicting classifications

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:: RCV001269544.12

Allele description [Variation Report for NM_000142.5(FGFR3):c.1612A>G (p.Ile538Val)]

NM_000142.5(FGFR3):c.1612A>G (p.Ile538Val)

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.1612A>G (p.Ile538Val)

HGVS:

NC_000004.12:g.1805636A>G
NG_012632.1:g.17325A>G
NM_000142.5:c.1612A>GMANE SELECT
NM_001163213.2:c.1618A>G
NM_001354809.2:c.1615A>G
NM_001354810.2:c.1615A>G
NM_022965.4:c.1276A>G
NP_000133.1:p.Ile538Val
NP_000133.1:p.Ile538Val
NP_001156685.1:p.Ile540Val
NP_001341738.1:p.Ile539Val
NP_001341739.1:p.Ile539Val
NP_075254.1:p.Ile426Val
LRG_1021t1:c.1612A>G
LRG_1021:g.17325A>G
LRG_1021p1:p.Ile538Val
NC_000004.11:g.1807363A>G
NM_000142.4:c.1612A>G
NR_148971.2:n.2038A>G
P22607:p.Ile538Val

Protein change:

I426V; ILE538VAL

Links:

UniProtKB: P22607#VAR_004157; OMIM: 134934.0019; dbSNP: rs80053154

NCBI 1000 Genomes Browser:

rs80053154

Molecular consequence:

NM_000142.5:c.1612A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001163213.2:c.1618A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354809.2:c.1615A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354810.2:c.1615A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_022965.4:c.1276A>G - missense variant - [Sequence Ontology: SO:0001583]
NR_148971.2:n.2038A>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Observations:

Condition(s)

Synonyms:: none provided; RECLASSIFIED - ADRA2C POLYMORPHISM; RECLASSIFIED - ADRB1 POLYMORPHISM
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001449602	Clinical Genetics and Genomics, Karolinska University Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 24, 2015)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002507705	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (May 12, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 10215410, 28763161, 30753492, 26992226, 28492532
SCV002578807	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (May 24, 2023)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001449602

Clinical Genetics and Genomics, Karolinska University Hospital

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Feb 24, 2015)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV002507705

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(May 12, 2024)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV002578807

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(May 24, 2023)

germline

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	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

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

A novel missense mutation Ile538Val in the fibroblast growth factor receptor 3 in hypochondroplasia. Mutations in brief no. 122. Online.

Grigelioniené G, Hagenäs L, Eklöf O, Neumeyer L, Haereid PE, Anvret M.

Hum Mutat. 1998;11(4):333.

PubMed [citation]

PMID:: 10215410

See all PubMed Citations (6)

Details of each submission

From Clinical Genetics and Genomics, Karolinska University Hospital, SCV001449602.1

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

#	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		1	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002507705.4

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

Description

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 538 of the FGFR3 protein (p.Ile538Val). This variant is present in population databases (rs80053154, gnomAD 0.005%). This missense change has been observed in individuals with clinical features of FGFR3-related conditions and/or clinical features of hypochondroplasia (PMID: 10215410, 28763161, 30753492; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 16345). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on FGFR3 protein function. Experimental studies have shown that this missense change affects FGFR3 function (PMID: 26992226). For these reasons, this variant has been classified as Pathogenic.

#	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

From GeneDx, SCV002578807.3

#	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 does not alter protein structure/function; This variant is associated with the following publications: (PMID: 10215410, 34006472, 34662886, 29758562, 29739731, 30753492, 35627109, 28763161)

#	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

Last Updated: May 16, 2025

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