ClinVar Miner

Submissions for variant NM_006270.5(RRAS):c.154-4C>G

gnomAD frequency: 0.00057  dbSNP: rs372925843
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000545294 SCV000629003 likely benign Noonan syndrome 2024-01-12 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001264470 SCV001442643 benign not specified 2020-10-19 criteria provided, single submitter clinical testing Variant summary: RRAS c.154-4C>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00051 in 238238 control chromosomes, predominantly at a frequency of 0.001 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 400-fold the estimated maximal expected allele frequency for a pathogenic variant in RRAS causing Noonan Syndrome And Related Conditions phenotype (2.5e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.154-4C>G in individuals affected with Noonan Syndrome And Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. Co-occurrence with another pathogenic variant has been reported (PTPN11 c.181G>A , p.Asp61Asn; internal sample), providing supporting evidence for a benign role. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and cited the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign.
GeneDx RCV001541535 SCV001759548 benign not provided 2021-05-08 criteria provided, single submitter clinical testing

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