ClinVar Miner

Submissions for variant NM_207361.6(FREM2):c.8176+2dup

gnomAD frequency: 0.00001  dbSNP: rs779126010
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Fulgent Genetics, Fulgent Genetics RCV001536062 SCV001752759 likely pathogenic Isolated cryptophthalmia; Fraser syndrome 2 2021-06-30 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002222716 SCV002500728 likely pathogenic Fraser syndrome 1 2022-03-28 criteria provided, single submitter clinical testing Variant summary: FREM2 c.8176+2dupT alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a 5' splicing donor site. One predict the variant weakens a 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 2e-05 in 250078 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.8176+2dupT in individuals affected with Cryptophthalmos Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Other splice site variants have been reported in association with Fraser syndrome (HGMD). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp RCV002568230 SCV003459634 uncertain significance not provided 2022-07-11 criteria provided, single submitter clinical testing This sequence change falls in intron 17 of the FREM2 gene. It does not directly change the encoded amino acid sequence of the FREM2 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs779126010, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with FREM2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1179176). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Revvity Omics, Revvity RCV002568230 SCV003833710 likely pathogenic not provided 2022-09-12 criteria provided, single submitter clinical testing

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