ClinVar Miner

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

gnomAD frequency: 0.00001  dbSNP: rs587782949
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen RASopathy Variant Curation Expert Panel RCV004760351 SCV000616400 uncertain significance RASopathy 2024-09-17 reviewed by expert panel curation The c.277A>G variant in the HRAS gene is a missense variant predicted to cause substitution of isoleucine by valine at amino acid 93 (p.Ile93Val). The highest population minor allele frequency in gnomAD v4.1.0 is 0.0002053% (2/63238 alleles) in the European (Finnish) population (PM2_Supporting/BS1/BA1 are not met). The computational predictor REVEL gives a score of 0.141 and does not predict a damaging effect on HRAS function (BP4). The c.277A>G (p.Ile93Val) variant has been identified in 1 patient with a features of a RASopathy, however an additional proband inherited this variant from an asymptomatic parent (PS4_Supporting not met, BS2 not met; GeneDx internal data, Blueprint Genetics internal data; GTR ID's: 26957, 500188; ClinVar SCV000207855.10, SCV000188770.2). In summary, this variant meets criteria to be classified as variant of uncertain significance for autosomal dominant RASopathies based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: BP4 (Specification Version 2.1, 09/17/2024)
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).
Labcorp Genetics (formerly Invitae), Labcorp RCV000524082 SCV003199645 uncertain significance Costello syndrome 2022-05-27 criteria provided, single submitter clinical testing This variant is present in population databases (rs587782949, gnomAD 0.004%). This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 93 of the HRAS protein (p.Ile93Val). This variant has not been reported in the literature in individuals affected with HRAS-related conditions. ClinVar contains an entry for this variant (Variation ID: 40439). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt HRAS protein function. 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.
Blueprint Genetics RCV000143899 SCV000188770 likely benign Pulmonic stenosis; Supravalvar aortic stenosis 2014-02-26 no assertion criteria provided clinical testing

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