ClinVar Miner

Submissions for variant NM_033360.4(KRAS):c.*12A>G (rs104894360)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 5
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare 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 likely pathogenic Rasopathy 2017-12-27 criteria provided, single submitter clinical testing 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. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with a KRAS-related disease. However, it has been observed to segregate in individuals with clinical features of KRAS-related disease in a family (Invitae). ClinVar contains an entry for this variant (Variation ID: 40465). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). 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. A different missense substitution at this codon (p.Asp153Val) has been determined to be pathogenic (PMID: 16474404, 16474405, 16773572). This suggests that the aspartic acid residue is critical for KRAS protein function and that other missense substitutions at this position may also be pathogenic. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Blueprint Genetics RCV000157939 SCV000928104 pathogenic not provided 2018-12-07 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001197968 SCV001368753 likely pathogenic Global developmental delay; Bilateral sensorineural hearing impairment; Delayed speech and language development; Delayed fine motor development 2016-01-01 criteria provided, single submitter clinical testing This variant was classified as: Uncertain significance. The following ACMG criteria were applied in classifying this variant: PM2,PP3. This variant was detected in hemizygous state.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.