ClinVar Miner

Submissions for variant NM_207361.6(FREM2):c.2128C>T (p.Arg710Cys) (rs41292753)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000173606 SCV000224730 likely benign not specified 2016-10-19 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000341512 SCV000384157 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.
Invitae RCV000872037 SCV001013787 likely benign not provided 2019-12-31 criteria provided, single submitter clinical testing
GeneDx RCV000872037 SCV001788032 uncertain significance not provided 2020-09-09 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000872037 SCV001554378 uncertain significance not provided no assertion criteria provided clinical testing The FREM2 p.Arg710Cys variant was not identified in the literature nor was it identified in Cosmic. The variant was identified in dbSNP (ID: rs41292753), ClinVar (classified as likely benign by EGL Genetic Diagnostics and as a VUS by Illumina Clinical Services for Cryptophthalmos syndrome), and LOVD 3.0. The variant was identified in control databases in 725 of 282732 chromosomes (1 homozygous) at a frequency of 0.002564 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: Other in 36 of 7224 chromosomes (freq: 0.004983), European (non-Finnish) in 535 of 129058 chromosomes (freq: 0.004145), Latino in 88 of 35434 chromosomes (freq: 0.002483), European (Finnish) in 40 of 25116 chromosomes (freq: 0.001593), Ashkenazi Jewish in 9 of 10368 chromosomes (freq: 0.000868) and African in 17 of 24962 chromosomes (freq: 0.000681), but was not observed in the East Asian or South Asian populations. The p.Arg710 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume 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. This variant is classified as a variant of uncertain significance.

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