Submissions for variant NM_025074.7(FRAS1):c.1918C>T (p.Arg640Cys)

gnomAD frequency: 0.00074  dbSNP: rs147869493

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001151397	SCV001312519	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.
CeGaT Center for Human Genetics Tuebingen	RCV001171737	SCV001334573	likely benign	not provided	2023-03-01	criteria provided, single submitter	clinical testing	FRAS1: BP4, BS2
Invitae	RCV001171737	SCV002434697	likely benign	not provided	2024-01-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002271622	SCV002555767	uncertain significance	not specified	2022-06-08	criteria provided, single submitter	clinical testing	Variant summary: FRAS1 c.1918C>T (p.Arg640Cys) results in a non-conservative amino acid change located in the Furin-like repeat (IPR006212) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00082 in 248996 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than expected for a pathogenic variant in FRAS1 causing Cryptophthalmos Syndrome (0.00082 vs 0.0018), allowing no conclusion about variant significance. c.1918C>T has been reported in the literature in individuals affected with Anopthalmia/Microphthalmia (Deml_2016) and multiple fetal abnormalities (Carss_2014). These reports 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. Three ClinVar submitters have assessed the variant since 2014: one classified the variant as of uncertain significance and two as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV003918742	SCV004733380	likely benign	FRAS1-related condition	2022-11-18	criteria provided, single submitter	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).
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001171737	SCV001743197	likely benign	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV001171737	SCV001800439	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001171737	SCV001972474	likely benign	not provided		no assertion criteria provided	clinical testing