ClinVar Miner

Submissions for variant NM_005343.4(HRAS):c.277A>G (p.Ile93Val) (rs587782949)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Blueprint Genetics RCV000143899 SCV000188770 likely benign Pulmonic stenosis; Supravalvar aortic stenosis 2014-02-26 no assertion criteria provided clinical testing
ClinGen RASopathy Variant Curation Expert Panel RCV000524082 SCV000616400 uncertain significance Costello syndrome 2017-04-03 reviewed by expert panel curation The c.277A>G (p.Ile93Val) variant has been identified in at least 2 independent occurrences in patients with a RASopathy (PS4_Supporting; GeneDx, Blueprint genetics internal data; GTR ID's: 26957, 500188 ClinVar SCV000207855; SCV000188770). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). In summary, the clinical significance of the p.Ile93Val variant is uncertain. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS4_Supporting, PM2.
GeneDx RCV000157920 SCV000207855 uncertain significance not provided 2013-02-26 criteria provided, single submitter clinical testing The I93V missense substitution has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The I93V amino acid substitution is conservative as both Isoleucine and Valine are neutral and non-polar residues. The residue at which this substitution occurs is highly conserved across species within this protein but not in related proteins. The NHLBI ESP Exome Variant Server reports that I93V was not observed in approximately 6,500 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. The vast majority of missense changes in HRAS are pathogenic; however, no other clear mutations have been reported in nearby codons. One other missense change (S89C) has been reported in a nearby codon, however its pathogenicity is questionable as an unaffected parent was also found to harbor this missense change (Gripp et al., 2012). Based on the currently available information, it is unclear whether I93V is a disease-causing mutation or a rare benign variant. This variant has been observed to be paternally inherited. The variant is found in NOONAN panel(s).

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