Submissions for variant NM_004985.5(KRAS):c.458A>G (p.Asp153Gly)

dbSNP: rs104894360

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000038274	SCV000061943	likely pathogenic	Noonan syndrome	2008-05-09	criteria provided, single submitter	clinical testing
GeneDx	RCV000157939	SCV000207874	pathogenic	not provided	2012-05-08	criteria provided, single submitter	clinical testing	The D153G missense mutation has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge; however, it was observed previously at GeneDx in another unrelated patient referred for testing. This amino acid substitution is non-conservative, as it results in a loss of charge and polarity. Another missense mutation at this position (D153V) has been reported in association with Noonan syndrome (Schubbert et al., 2006) and in the allelic disorder Cardio-Facio-Cutaneous syndrome (Niihori et al., 2006). Therefore, D153G is considered to be a pathogenic mutation, and its presence is consistent with a diagnosis of an autosomal dominant KRAS-related disorder. The variant is found in NOONAN panel(s).
Invitae	RCV000526276	SCV000659086	pathogenic	RASopathy	2020-10-01	criteria provided, single submitter	clinical testing	This variant disrupts the p.Asp153 amino acid residue in KRAS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16474404, 16474405, 16773572). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). This variant has been observed in individual(s) with KRAS-related conditions (PMID: 29758562, Invitae). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 40465). This variant is not present in population databases (ExAC no frequency). This sequence change replaces aspartic acid with glycine at codon 153 of the KRAS protein (p.Asp153Gly). The aspartic acid residue is weakly conserved and there is a moderate physicochemical difference between aspartic acid and glycine.
Blueprint Genetics	RCV000157939	SCV000928104	pathogenic	not provided	2018-12-07	criteria provided, single submitter	clinical testing