8-38426158-C-T
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The ENST00000447712.7(FGFR1):c.709G>A(p.Gly237Ser) variant causes a missense change involving the alteration of a conserved nucleotide. 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G237D) has been classified as Pathogenic.
Frequency
Consequence
ENST00000447712.7 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 19 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
FGFR1 | NM_023110.3 | c.709G>A | p.Gly237Ser | missense_variant | 6/18 | ENST00000447712.7 | NP_075598.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
FGFR1 | ENST00000447712.7 | c.709G>A | p.Gly237Ser | missense_variant | 6/18 | 1 | NM_023110.3 | ENSP00000400162 | P4 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Hypogonadotropic hypogonadism 2 with or without anosmia Pathogenic:1Other:1
risk factor, no assertion criteria provided | literature only | OMIM | Apr 18, 2006 | - - |
Likely pathogenic, criteria provided, single submitter | research | Reproductive Endocrine Unit, Massachusetts General Hospital | May 04, 2023 | - - |
FGFR1-related disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 22, 2022 | Variant summary: FGFR1 c.709G>A (p.Gly237Ser) results in a non-conservative amino acid change located in the Immunoglobulin subtype 2 domain (IPR003598) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250914 control chromosomes (gnomAD and publication data). c.709G>A has been reported in the literature in individuals affected with idiopathic hypogonadotropic hypogonadism as well as in two unaffected individuals (Pitteloud_2006, Shaw_2011, Wang_2014, Wang_2017, Men_2019). These data indicate that the variant is likely to be associated with disease. At least one functional study reports this variant results in inhibiting proper folding of the FGFR1 and likely leading to the loss of cell-surface expression of FGFR1 (Pitteloud_2006). Additionally, another missense variant at the same codon, G237D, has been found in patients with Kallmann syndrome and segregated with the disease in one family (PMID: 16764984), indicating this residue is critical for FGFR1 protein function. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at