Submissions for variant NM_207361.6(FREM2):c.4031G>A (p.Arg1344His)

gnomAD frequency: 0.00430  dbSNP: rs143044921

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000406982	SCV000384181	likely benign	Fraser syndrome 2	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	RCV000872025	SCV001013774	benign	not provided	2025-01-23	criteria provided, single submitter	clinical testing
Johns Hopkins Genomics, Johns Hopkins University	RCV000406982	SCV001438367	benign	Fraser syndrome 2	2020-09-24	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002502225	SCV002808898	likely benign	Isolated cryptophthalmia; Fraser syndrome 2	2022-04-06	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000872025	SCV004033257	likely benign	not provided	2023-07-01	criteria provided, single submitter	clinical testing	FREM2: BP4
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003488525	SCV004241017	benign	not specified	2023-12-12	criteria provided, single submitter	clinical testing	Variant summary: FREM2 c.4031G>A (p.Arg1344His) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0035 in 251390 control chromosomes in the gnomAD database, including 10 homozygotes. The observed variant frequency is approximately 2.8 fold of the estimated maximal expected allele frequency for a pathogenic variant in FREM2 causing Cryptophthalmos Syndrome phenotype (0.0013), strongly suggesting that the variant is benign. To our knowledge, no penetrant association of c.4031G>A in individuals affected with Cryptophthalmos Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Based on the evidence outlined above, the variant was classified as benign.
Breakthrough Genomics, Breakthrough Genomics	RCV000872025	SCV005215569	likely benign	not provided		criteria provided, single submitter	not provided
Daryl Scott Lab, Baylor College of Medicine	RCV000577937	SCV000484665	risk factor	Congenital diaphragmatic hernia	2016-11-09	no assertion criteria provided	research
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000872025	SCV001799201	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000872025	SCV001926891	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000872025	SCV001969477	likely benign	not provided		no assertion criteria provided	clinical testing
Yale Center for Mendelian Genomics, Yale University	RCV001849364	SCV002106503	likely pathogenic	Congenital anomaly of kidney and urinary tract	2018-08-24	no assertion criteria provided	literature only
PreventionGenetics, part of Exact Sciences	RCV003910163	SCV004720777	benign	FREM2-related disorder	2021-01-05	no assertion criteria provided	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).