Submissions for variant NM_025074.7(FRAS1):c.4579C>T (p.Arg1527Trp)

gnomAD frequency: 0.00253  dbSNP: rs1872267

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000658999	SCV000229750	uncertain significance	not provided	2018-03-23	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000388525	SCV000451203	likely benign	Fraser syndrome 1	2018-01-12	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.
CeGaT Center for Human Genetics Tuebingen	RCV000658999	SCV000780802	likely benign	not provided	2024-08-01	criteria provided, single submitter	clinical testing	FRAS1: BP4, BS1
Labcorp Genetics (formerly Invitae), Labcorp	RCV000658999	SCV001013434	likely benign	not provided	2025-01-30	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001818432	SCV002064903	uncertain significance	not specified	2019-07-12	criteria provided, single submitter	clinical testing
GeneDx	RCV000658999	SCV002104349	uncertain significance	not provided	2023-04-11	criteria provided, single submitter	clinical testing	Identified in unrelated individuals with congenital anomalies of the kidney and urinary tract who had second variants detected, however phase was not confirmed (Kohl et al., 2014); Reported with a second FRAS1 variant, phase unknown, in a patient with bilateral Peter's anomaly (Chesneau et al., 2022); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28542843, 34426522, 33726816, 24700879, 35170016)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001818432	SCV002598960	likely benign	not specified	2022-09-06	criteria provided, single submitter	clinical testing	Variant summary: FRAS1 c.4579C>T (p.Arg1527Trp) 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 0.0028 in 249038 control chromosomes in the gnomAD database, including 2 homozygotes. The observed variant frequency is approximately 2 fold of the estimated maximal predicted allele frequency for a pathogenic variant in FRAS1 causing Cryptophthalmos Syndrome phenotype (0.0018), strongly suggesting that the variant is benign. c.4579C>T has been reported in the literature in individuals affected Congenital anomalies of the kidney and urinary tract (example: Kohl_2014). This report does 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. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=4) and likely benign (n=2). Based on the evidence outlined above, the variant was classified as likely benign.
Ambry Genetics	RCV004619207	SCV005118749	likely benign	Inborn genetic diseases	2024-05-20	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000658999	SCV001797398	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000658999	SCV001927295	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000658999	SCV001967179	likely benign	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003977456	SCV004787380	likely benign	FRAS1-related disorder	2020-10-12	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).