Submissions for variant NM_025074.7(FRAS1):c.5725G>A (p.Val1909Ile)

gnomAD frequency: 0.00049  dbSNP: rs182652779

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001727970	SCV002185374	uncertain significance	not provided	2025-01-13	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1909 of the FRAS1 protein (p.Val1909Ile). This variant is present in population databases (rs182652779, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with FRAS1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1284950). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt FRAS1 protein function with a negative predictive value of 80%. 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.
Ambry Genetics	RCV004039955	SCV004872723	uncertain significance	Inborn genetic diseases	2022-06-09	criteria provided, single submitter	clinical testing	The c.5725G>A (p.V1909I) alteration is located in exon 42 (coding exon 42) of the FRAS1 gene. This alteration results from a G to A substitution at nucleotide position 5725, causing the valine (V) at amino acid position 1909 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001703077	SCV001928341	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001727970	SCV001969453	likely benign	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003968489	SCV004788363	likely benign	FRAS1-related disorder	2024-02-29	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).