Submissions for variant NM_207361.6(FREM2):c.8902G>A (p.Val2968Ile)

gnomAD frequency: 0.00379  dbSNP: rs116099212

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000176440	SCV000228096	benign	not specified	2014-12-01	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000224494	SCV000281126	likely benign	not provided	2015-09-29	criteria provided, single submitter	clinical testing	Converted during submission to Likely benign.
Invitae	RCV000224494	SCV001012437	benign	not provided	2024-01-31	criteria provided, single submitter	clinical testing
Mendelics	RCV000989101	SCV001139298	benign	Fraser syndrome 1	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001110834	SCV001268316	likely benign	Fraser syndrome 2	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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
GeneDx	RCV000224494	SCV001782781	likely benign	not provided	2019-09-09	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26275891)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000176440	SCV002555646	benign	not specified	2022-06-03	criteria provided, single submitter	clinical testing	Variant summary: FREM2 c.8902G>A (p.Val2968Ile) results in a conservative amino acid change in 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 0.0041 in 282828 control chromosomes in the gnomAD database, with 6 homozygotes. The variant occurs predominantly at a frequency of 0.0063 within the Non-Finnish European subpopulation in the gnomAD database, with 3 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 5 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 a benign polymorphism found primarily in populations of Non-Finnish European origin. Five ClinVar submitters have assessed the variant since 2014: three classified the variant as likely benign and two as benign. Based on the evidence outlined above, the variant was classified as benign.
Fulgent Genetics, Fulgent Genetics	RCV002500488	SCV002812629	likely benign	Isolated cryptophthalmia; Fraser syndrome 2	2022-04-08	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000224494	SCV004133069	likely benign	not provided	2023-08-01	criteria provided, single submitter	clinical testing	FREM2: BP4, BS2
PreventionGenetics, part of Exact Sciences	RCV003917638	SCV004729282	likely benign	FREM2-related condition	2019-05-06	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).
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000224494	SCV001548862	likely benign	not provided		no assertion criteria provided	clinical testing	The FREM2 p.Val2968Ile variant was not identified in Cosmic but was identified in dbSNP (ID: rs116099212), ClinVar (classified as benign by EGL Genetic Diagnostics and likely benign by Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics) and LOVD 3.0 (classified as likely benign). The variant was identified in control databases in 1149 of 282828 chromosomes (6 homozygous) at a frequency of 0.004063 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 811 of 129136 chromosomes (freq: 0.00628), South Asian in 154 of 30616 chromosomes (freq: 0.00503), Other in 28 of 7226 chromosomes (freq: 0.003875), European (Finnish) in 67 of 25122 chromosomes (freq: 0.002667), Latino in 61 of 35438 chromosomes (freq: 0.001721), African in 24 of 24974 chromosomes (freq: 0.000961), Ashkenazi Jewish in 3 of 10364 chromosomes (freq: 0.00029), and East Asian in 1 of 19952 chromosomes (freq: 0.00005). This variant was identified in the heterozygous state in one case with a prenatal diagnosis of laryngeal atresia/stenosis although the clinical significance of this variant is not known (Drury_2015_PMID:26275891). The p.Val2968 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. 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. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.