NM_023110.3(FGFR1):c.1271G>A (p.Arg424His) AND multiple conditions

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Dec 3, 2024
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:: RCV003786770.3

Allele description [Variation Report for NM_023110.3(FGFR1):c.1271G>A (p.Arg424His)]

NM_023110.3(FGFR1):c.1271G>A (p.Arg424His)

Gene:

FGFR1:fibroblast growth factor receptor 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

8p11.23

Genomic location:

Preferred name:

NM_023110.3(FGFR1):c.1271G>A (p.Arg424His)

HGVS:

NC_000008.11:g.38419546C>T
NG_007729.1:g.54289G>A
NM_000604.2:c.1271G>A
NM_001174063.2:c.1271G>A
NM_001174064.2:c.1247G>A
NM_001174065.2:c.1265G>A
NM_001174066.2:c.1004G>A
NM_001174067.2:c.1364G>A
NM_001354367.2:c.1265G>A
NM_001354368.2:c.998G>A
NM_001354369.2:c.1265G>A
NM_001354370.2:c.998G>A
NM_001410922.1:c.1265G>A
NM_015850.4:c.1265G>A
NM_023105.3:c.1004G>A
NM_023106.3:c.998G>A
NM_023110.3:c.1271G>AMANE SELECT
NP_000595.1:p.Arg424His
NP_001167534.1:p.Arg424His
NP_001167535.1:p.Arg416His
NP_001167536.1:p.Arg422His
NP_001167537.1:p.Arg335His
NP_001167538.1:p.Arg455His
NP_001341296.1:p.Arg422His
NP_001341297.1:p.Arg333His
NP_001341298.1:p.Arg422His
NP_001341299.1:p.Arg333His
NP_001397851.1:p.Arg422His
NP_056934.2:p.Arg422His
NP_075593.1:p.Arg335His
NP_075594.1:p.Arg333His
NP_075598.2:p.Arg424His
NP_075598.2:p.Arg424His
LRG_993t1:c.1271G>A
LRG_993:g.54289G>A
LRG_993p1:p.Arg424His
NC_000008.10:g.38277064C>T
NM_023110.2:c.1271G>A

Protein change:

R333H

Links:

dbSNP: rs183376882

NCBI 1000 Genomes Browser:

rs183376882

Molecular consequence:

NM_000604.2:c.1271G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001174063.2:c.1271G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001174064.2:c.1247G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001174065.2:c.1265G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001174066.2:c.1004G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001174067.2:c.1364G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354367.2:c.1265G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354368.2:c.998G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354369.2:c.1265G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354370.2:c.998G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001410922.1:c.1265G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_015850.4:c.1265G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_023105.3:c.1004G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_023106.3:c.998G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_023110.3:c.1271G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hypogonadotropic hypogonadism 2 with or without anosmia (HH2)
Synonyms:: HYPOGONADOTROPIC HYPOGONADISM 2 WITHOUT ANOSMIA; HYPOGONADOTROPIC HYPOGONADISM 2 WITH OR WITHOUT ANOSMIA, SUSCEPTIBILITY TO; HYPOGONADOTROPIC HYPOGONADISM 2 WITHOUT ANOSMIA, SUSCEPTIBILITY TO
Identifiers:: MONDO: MONDO:0007844; MedGen: C1563720; Orphanet: 478; OMIM: 147950

Name:: Pfeiffer syndrome (ACS5)
Synonyms:: ACS V
Identifiers:: MONDO: MONDO:0007043; MedGen: C0220658; Orphanet: 710; OMIM: 101600

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004573317	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 3, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 33548149, 37805574, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004573317

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Dec 3, 2024)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

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

Novel rare variants in FGFR1 and clinical characteristics analysis in a series of congenital hypogonadotropic hypogonadism patients.

Nie M, Yu B, Chen R, Sun B, Mao J, Wang X, Zhang H, Wu X.

Clin Endocrinol (Oxf). 2021 Jul;95(1):153-162. doi: 10.1111/cen.14436. Epub 2021 Apr 30.

PubMed [citation]

PMID:: 33548149

How human genetic context can inform pathogenicity classification: FGFR1 variation in idiopathic hypogonadotropic hypogonadism.

Xu W, Plummer L, Seminara SB, Balasubramanian R, Lippincott MF.

Hum Genet. 2023 Nov;142(11):1611-1619. doi: 10.1007/s00439-023-02601-w. Epub 2023 Oct 7.

PubMed [citation]

PMID:: 37805574
PMCID:: PMC10977353

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004573317.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 424 of the FGFR1 protein (p.Arg424His). This variant is present in population databases (rs183376882, gnomAD 0.02%). This missense change has been observed in individuals with Kallmann syndrome (PMID: 33548149). ClinVar contains an entry for this variant (Variation ID: 2927948). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt FGFR1 protein function with a negative predictive value of 80%. This variant disrupts the p.Arg424 amino acid residue in FGFR1. Other variant(s) that disrupt this residue have been observed in individuals with FGFR1-related conditions (PMID: 33548149, 37805574), which suggests that this may be a clinically significant amino acid residue. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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: May 16, 2025

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