ClinVar Miner

Submissions for variant NM_006939.4(SOS2):c.2854G>A (p.Asp952Asn) (rs200387871)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000652821 SCV000774693 likely benign Noonan syndrome 9 2020-11-25 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001193657 SCV001362636 benign not specified 2021-04-08 criteria provided, single submitter clinical testing Variant summary: SOS2 c.2854G>A (p.Asp952Asn) results in a conservative amino acid change located in the Ras guanine-nucleotide exchange factors catalytic domain (IPR001895) of 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 0.00032 in 227036 control chromosomes, predominantly at a frequency of 0.0012 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 480-fold of the estimated maximal expected allele frequency for a pathogenic variant in SOS2 causing Noonan Syndrome And Related Conditions phenotype (2.5e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. c.2854G>A has been reported in the literature in an individual affected with RASopathy disorder and was described by the authors as "Likely disease-unrelated" (Cordeddu_2015), while it was also detected in another RASopathy-like sample co-occurring with a pathogenic variant (RAF1 c.770C>T, p.Ser257Leu; Castellanos_2020). Furthermore, the variant was detected in a case with metachondromatosis (Bowen_2011) and it was also detected in unaffected controls without Noonan Syndrome phenotype (Yamamoto_2015). These reports do not support association of the variant with Noonan Syndrome and Related Conditions. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submitter (evaluation after 2014) cites the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign.

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