rs1554570706
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1PM2PP2PP3_ModeratePP5_Very_Strong
The NM_023110.3(FGFR1):c.232C>T(p.Arg78Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_023110.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 15 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
FGFR1 | ENST00000447712.7 | c.232C>T | p.Arg78Cys | missense_variant | Exon 3 of 18 | 1 | NM_023110.3 | ENSP00000400162.2 | ||
FGFR1 | ENST00000397091.9 | c.232C>T | p.Arg78Cys | missense_variant | Exon 3 of 18 | 1 | ENSP00000380280.5 | |||
FGFR1 | ENST00000397108.8 | c.232C>T | p.Arg78Cys | missense_variant | Exon 4 of 19 | 1 | ENSP00000380297.4 | |||
FGFR1 | ENST00000397113.6 | c.232C>T | p.Arg78Cys | missense_variant | Exon 3 of 18 | 2 | ENSP00000380302.2 | |||
FGFR1 | ENST00000356207.9 | c.92-1373C>T | intron_variant | Intron 2 of 16 | 1 | ENSP00000348537.5 | ||||
FGFR1 | ENST00000397103.5 | c.92-1373C>T | intron_variant | Intron 1 of 15 | 5 | ENSP00000380292.1 | ||||
FGFR1 | ENST00000326324.10 | c.92-1373C>T | intron_variant | Intron 2 of 16 | 1 | ENSP00000327229.6 | ||||
FGFR1 | ENST00000487647.5 | n.92-418C>T | intron_variant | Intron 1 of 11 | 1 | ENSP00000435254.1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Cov.: 32
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Hypogonadotropic hypogonadism 2 with or without anosmia Pathogenic:2
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FGFR1-related disorder Pathogenic:1
The FGFR1 c.232C>T variant is predicted to result in the amino acid substitution p.Arg78Cys. This variant has been reported in multiple individuals with Kallmann syndrome and hypogonadotropic hypogonadism (Pitteloud et al. 2006. PubMed ID: 16764984; Miraoui H et al. 2013. PubMed ID: 23643382; Xu C et al. 2017. PubMed ID: 28754744; Cassatella D et al. 2018. PubMed ID: 29419413; Gach A et al. 2020. PubMed ID: 31996231; Liu Q et al. 2022. PubMed ID: 35090434). In at least one individual, this variant was found to have arisen de novo (Liu Q et al. 2022. PubMed ID: 35090434). One functional study showed that this variant evoked a decreased response (Xu C et al. 2017. PubMed ID: 28754744). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as likely pathogenic. -
not provided Pathogenic:1
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as c.331C>T, p.(R111C); This variant is associated with the following publications: (PMID: 23643382, 16764984, 28754744, 31996231, 35090434, 34348883, 23329143, 29419413, 37805574) -
Pfeiffer syndrome;C1563720:Hypogonadotropic hypogonadism 2 with or without anosmia Pathogenic:1
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 78 of the FGFR1 protein (p.Arg78Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypogonadotropic hypogonadism and Kallmann syndrome (PMID: 16764984, 23643382, 28754744; Invitae). ClinVar contains an entry for this variant (Variation ID: 431966). 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 FGFR1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects FGFR1 function (PMID: 28754744). For these reasons, this variant has been classified as Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at