Submissions for variant NM_023110.3(FGFR1):c.274G>A (p.Val92Met)

gnomAD frequency: 0.00001  dbSNP: rs755828990

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001163225	SCV001325244	benign	Trigonocephaly 1	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Illumina Laboratory Services, Illumina	RCV001163226	SCV001325245	benign	Osteoglophonic dysplasia	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Illumina Laboratory Services, Illumina	RCV001163227	SCV001325246	benign	Craniosynostosis syndrome	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Illumina Laboratory Services, Illumina	RCV001165321	SCV001327505	likely benign	Hypogonadotropic hypogonadism 2 with or without anosmia	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002557393	SCV003260007	uncertain significance	Hypogonadotropic hypogonadism 2 with or without anosmia; Pfeiffer syndrome	2023-09-10	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 92 of the FGFR1 protein (p.Val92Met). 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. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on FGFR1 protein function. ClinVar contains an entry for this variant (Variation ID: 911004). This variant has not been reported in the literature in individuals affected with FGFR1-related conditions. This variant is present in population databases (rs755828990, gnomAD 0.03%), and has an allele count higher than expected for a pathogenic variant.
PreventionGenetics, part of Exact Sciences	RCV004538383	SCV004717357	uncertain significance	FGFR1-related disorder	2023-11-01	criteria provided, single submitter	clinical testing	The FGFR1 c.274G>A variant is predicted to result in the amino acid substitution p.Val92Met. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.030% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/8-38287284-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.