Submissions for variant NM_023110.3(FGFR1):c.1328T>C (p.Leu443Pro)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV002800109	SCV003026962	uncertain significance	Hypogonadotropic hypogonadism 2 with or without anosmia; Pfeiffer syndrome	2022-09-26	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 443 of the FGFR1 protein (p.Leu443Pro). This variant is present in population databases (rs756375285, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with FGFR1-related conditions. 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. 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	RCV003155491	SCV003844291	uncertain significance	not specified	2023-02-27	criteria provided, single submitter	clinical testing	Variant summary: FGFR1 c.1328T>C (p.Leu443Pro) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 249446 control chromosomes (i.e. 11 carriers; gnomAD v2.1 exomes dataset). The available data on variant occurrences in the general population are insufficient to allow clear conclusions about variant significance. To our knowledge, no occurrence of c.1328T>C in individuals affected with FGFR1-Related Disorders and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
PreventionGenetics, part of Exact Sciences	RCV004545389	SCV004775803	uncertain significance	FGFR1-related disorder	2024-01-04	criteria provided, single submitter	clinical testing	The FGFR1 c.1328T>C variant is predicted to result in the amino acid substitution p.Leu443Pro. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.032% of alleles in individuals of Latino descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.