Submissions for variant NM_004985.5(KRAS):c.101C>G (p.Pro34Arg)

dbSNP: rs104894366

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000211723	SCV000061924	likely pathogenic	Noonan syndrome; Cardio-facio-cutaneous syndrome	2015-08-21	criteria provided, single submitter	clinical testing	The p.Pro34Arg in KRAS variant has been reported 1 adolescent with clinical feat ures of Cardio-facio-cutaneous syndrome as a de novo occurrence (Schubbert 2006) and by our laboratory in 1 child with clinical features of Noonan syndrome (LMM unpublished data). It was absent from large population studies. In vitro functi onal studies provide evidence that the p.Pro34Arg may impact protein function (S tone 1993, Schubbert 2007, Gremer 2010). However, these types of assays may not accurately represent biological function. In summary, although additional studie s are required to fully establish its clinical significance, the p.Pro34Arg vari ant is likely pathogenic.
Molecular Diagnostics Lab, Nemours Children's Health, Delaware	RCV000207495	SCV000263050	pathogenic	not provided	2015-07-20	criteria provided, single submitter	clinical testing
GeneDx	RCV000207495	SCV000329384	pathogenic	not provided	2022-06-14	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect through constitutive phosphorylation of MEK, ERK, AKT and S6; supporting a gain of function mechanism (Gremer et al., 2011; Schubbert et al., 2007); Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 28958387, 20949621, 24803665, 31216405, 17875937, 16474405)
Baylor Genetics	RCV000850569	SCV000992785	pathogenic	Noonan syndrome 3; Autoimmune lymphoproliferative syndrome type 4; Acute myeloid leukemia; Cardiofaciocutaneous syndrome 2	2017-12-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001851825	SCV002159858	pathogenic	RASopathy	2021-12-22	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Pro34 amino acid residue in KRAS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17056636). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects KRAS function (PMID: 20949621). 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 expected to disrupt KRAS protein function. ClinVar contains an entry for this variant (Variation ID: 12590). This missense change has been observed in individual(s) with cardio-facio-cutaneous syndrome (PMID: 16474405). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 34 of the KRAS protein (p.Pro34Arg).
OMIM	RCV000043674	SCV000033668	pathogenic	Cardiofaciocutaneous syndrome 2	2006-03-01	no assertion criteria provided	literature only