Submissions for variant NM_025074.7(FRAS1):c.9364C>T (p.Arg3122Trp)

gnomAD frequency: 0.00046  dbSNP: rs200346497

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000179606	SCV000231878	uncertain significance	not provided	2018-03-23	criteria provided, single submitter	clinical testing
Paul Sabatier University EA-4555, Paul Sabatier University	RCV000207380	SCV000259163	likely benign	Anophthalmia-microphthalmia syndrome	2013-01-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001151994	SCV001313186	uncertain significance	Fraser syndrome 1	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Invitae	RCV000179606	SCV002174458	uncertain significance	not provided	2022-10-13	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 3122 of the FRAS1 protein (p.Arg3122Trp). This variant is present in population databases (rs200346497, gnomAD 0.09%). This missense change has been observed in individual(s) with clinical features of Frasier syndrome (PMID: 24700879). ClinVar contains an entry for this variant (Variation ID: 198324). 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 FRAS1 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	RCV003488431	SCV004240999	uncertain significance	not specified	2023-12-12	criteria provided, single submitter	clinical testing	Variant summary: FRAS1 c.9364C>T (p.Arg3122Trp) results in a non-conservative amino acid change located in the Na-Ca exchanger/integrin-beta4 (IPR003644) of 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 0.00029 in 247584 control chromosomes, predominantly at a frequency of 0.00088 within the Latino subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in FRAS1 causing Cryptophthalmos Syndrome (0.00029 vs 0.0018), allowing no conclusion about variant significance. c.9364C>T has been reported in the literature as a single heterozygous change in individuals affected with isolated congenital anomalies of the kidney and urinary tract, without strong evidence for causality (example, Kohl_2014, Seltzsam_2022, Wang_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Cryptophthalmos Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 24700879, 34906515, 31308072). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
CeGaT Center for Human Genetics Tuebingen	RCV000179606	SCV004701511	uncertain significance	not provided	2024-01-01	criteria provided, single submitter	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000179606	SCV001797620	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000179606	SCV001959753	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000179606	SCV001965564	uncertain significance	not provided		no assertion criteria provided	clinical testing