Submissions for variant NM_207361.6(FREM2):c.8509C>T (p.Pro2837Ser)

gnomAD frequency: 0.00004  dbSNP: rs766715445

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000268713	SCV000384247	uncertain significance	Fraser syndrome 2	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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Fulgent Genetics, Fulgent Genetics	RCV002487382	SCV002776924	uncertain significance	Isolated cryptophthalmia; Fraser syndrome 2	2022-01-14	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001356115	SCV004512430	likely benign	not provided	2024-01-30	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356115	SCV001551188	uncertain significance	not provided		no assertion criteria provided	clinical testing	The FREM2 p.Pro2837Ser variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs766715445) and in ClinVar (classified as a VUS by Illumina Clinical Services Laboratories for Cryptophthalmos syndrome). The variant was also found in 34 of 282696 chromosomes at a frequency of 0.00012 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 29 of 10364 chromosomes (freq: 0.002798), African in 1 of 24964 chromosomes (freq: 0.00004), Latino in 1 of 35436 chromosomes (freq: 0.000028) and European (non-Finnish) in 3 of 129030 chromosomes (freq: 0.000023); it was not observed in the East Asian, European (Finnish), Other and South Asian populations. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Pro2837 residue is conserved in mammals and 4 of 5 computational analyses (PolyPhen-2, SIFT, BLOSUM, MutationTaster) suggest that the variant may impact the protein. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV003950060	SCV004763983	likely benign	FREM2-related disorder	2022-12-10	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).