ClinVar Miner

Submissions for variant NM_023110.3(FGFR1):c.621+4C>T

gnomAD frequency: 0.00001  dbSNP: rs750639887
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001940325 SCV002195166 uncertain significance Hypogonadotropic hypogonadism 2 with or without anosmia; Pfeiffer syndrome 2023-12-11 criteria provided, single submitter clinical testing This sequence change falls in intron 5 of the FGFR1 gene. It does not directly change the encoded amino acid sequence of the FGFR1 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs750639887, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with FGFR1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1418016). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV004690174 SCV005184461 uncertain significance not specified 2024-05-31 criteria provided, single submitter clinical testing Variant summary: FGFR1 c.621+4C>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.2e-05 in 249514 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.621+4C>T in individuals affected with FGFR1-Related Disorders and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 1418016). Based on the evidence outlined above, the variant was classified as uncertain significance.

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