ClinVar Miner

Submissions for variant NM_004985.5(KRAS):c.179G>T (p.Gly60Val) (rs727503108)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212500 SCV000207871 pathogenic not provided 2017-11-07 criteria provided, single submitter clinical testing The G60V variant has been reported as an apparently de novo variant in an infant who exhibited a severe phenotype and expired due to hypertrophic cardiomyopathy (Nosan et al., 2013). It has also been observed at GeneDx to occur apparently de novo in an affected patient. The variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). G60V occurs at a highly conserved position within the Switch II domain (Schubbert et al., 2007). In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in the same residue (G60S/R) and in a nearby residue (T58I) have been reported in the Human Gene Mutation Database in association with Noonan spectrum disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. In summary, we consider this variant to be pathogenic.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000150889 SCV000198468 likely pathogenic Non-small cell lung cancer 2013-07-19 no assertion criteria provided clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000157936 SCV000198469 likely pathogenic Noonan syndrome; Cardio-facio-cutaneous syndrome 2013-07-19 no assertion criteria provided clinical testing The Gly60Val variant in KRAS has not been previously identified in our laborator y, nor has this specific variant been reported in the literature in individuals with clinical features of Noonan spectrum disorders. However, two different amin o acid changes at the same codon, Gly60Arg and Gly60Ser, have been reported in t wo individuals with Cardio-facio-cutaneous syndrome and Noonan syndrome, respect ively (CFC; Niihori 2006, Kratz 2009). Parental testing confirmed the Gly60Ser h ad occured de novo in that patient (Kratz 2009). This variant has been observed to occur as a somatic change in two metastatic colorectal cancer tissues and ot her variants at this codon have been identified as somatic changes in other tiss ue types (Okayama 2011, Guedes 2013, COSMIC database). Functional studies sugges t the Gly60 is an important residue since it interacts with ?-phosphate of GTP a nd is a conserved amino acid across the superfamily of GTPases (Guedes 2013). Fu rthermore, this variant was absent in large, ethnically-distinct populations. Co mputational analyses (biochemical amino acid properties, conservation, AlignGVGD , PolyPhen2, and SIFT) suggest that the Gly60Val variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, this variant is likely pathogenic, though additional studies are requi red to fully establish its clinical significance.

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