ClinVar Miner

Submissions for variant NM_005343.4(HRAS):c.35G>A (p.Gly12Asp) (rs104894230)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000038460 SCV000062136 pathogenic Costello syndrome 2011-03-09 criteria provided, single submitter clinical testing The Gly12Asp variant in HRAS has been reported in the literature in four individ uals with severe neonatal Costello syndrome (Lo 2008, Kuniba 2009, Sinico 2010). This variant has been reported to have occurred de novo in two probands (Lo 200 8, Sinico 2010). This variant has been observed as a somatic change in tumor tis sue. Several other variants in codon 12 of HRAS are commonly observed in Costell o syndrome patients (Lin 2011). Therefore, it is highly likely that this variant is pathogenic.
GeneDx RCV000212496 SCV000207844 pathogenic not provided 2018-07-04 criteria provided, single submitter clinical testing The G12D variant in the HRAS gene has been reported previously as de novo and in association with Costello syndrome (Lo et al., 2008; Lorenz et al., 2012). Functional studies show G12D results in increased levels of the active, GTP-bound HRAS protein (Niihori et al., 2011). This variant is not observed in large population cohorts (Lek et al., 2016). The G12D variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Multiple pathogenic missense variants at this residue (G12S, G12C, G12V, G12A) have been reported in association with Costello syndrome (Aoki et al., 2005; Kerr et al., 2006).
Integrated Genetics/Laboratory Corporation of America RCV000149830 SCV000919525 pathogenic Rasopathy 2017-10-30 criteria provided, single submitter clinical testing Variant summary: The HRAS c.35G>A (p.Gly12Asp) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant is absent in 276492 control chromosomes. It has been reported in many CS cases and most of them with severe clinical presentations. Functional assays showed the variant to have increased activity (Niihori_2011). Variants involving codon 12 (such as p.G12S, p.G12A, p.G12C, p.G12D) have been reported in numerous affected individuals indicating it is mutation hotspot. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000038460 SCV001204990 pathogenic Costello syndrome 2019-06-09 criteria provided, single submitter clinical testing This sequence change replaces glycine with aspartic acid at codon 12 of the HRAS protein (p.Gly12Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. This variant is not present in population databases (ExAC no frequency). This variant has been observed in many individuals affected with Costello syndrome (PMID: 26916728, 18642361, 21850009, 27102959, 18039947, 22926243). In several individuals the variant was found to be de novo. ClinVar contains an entry for this variant (Variation ID: 12612). This variant has been reported to affect HRAS protein function (PMID: 24224811, 21850009). This variant disrupts the p.Gly12 amino acid residue in HRAS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16170316, 20979192, 21834037, 21850009, 22317973, 23751039). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000212496 SCV001247462 pathogenic not provided 2019-05-01 criteria provided, single submitter clinical testing
OMIM RCV000013446 SCV000033693 pathogenic Costello syndrome, severe 2012-06-10 no assertion criteria provided literature only
OMIM RCV000029210 SCV000051856 pathogenic Nevus sebaceous 2012-06-10 no assertion criteria provided literature only
Baylor Genetics RCV000149830 SCV000196674 pathogenic Rasopathy no assertion criteria provided clinical testing Variant classified using ACMG guidelines
Database of Curated Mutations (DoCM) RCV000429375 SCV000505662 likely pathogenic Neoplasm of the breast 2015-07-14 no assertion criteria provided literature only

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