ClinVar Miner

Submissions for variant NM_033360.4(KRAS):c.389C>T (p.Ala130Val) (rs730880473)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000157950 SCV000207885 uncertain significance not provided 2017-10-03 criteria provided, single submitter clinical testing A variant of unknown significance has been identified in the KRAS gene. The A130V variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The A130V variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. However, the A130V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Additionally, missense mutations in nearby residues have not been reported, indicating this region of the protein may tolerate change. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant.The variant is found in CARDIOMYOPATHY panel(s).
Illumina Clinical Services Laboratory,Illumina RCV000349904 SCV000377748 uncertain significance Noonan syndrome 2016-06-14 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001280675 SCV001467971 uncertain significance not specified 2020-12-21 criteria provided, single submitter clinical testing Variant summary: KRAS c.389C>T (p.Ala130Val) results in a non-conservative amino acid change located in the Small GTP-binding protein domain (IPR005225) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251168 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.389C>T in individuals affected with Noonan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV001368828 SCV001565242 uncertain significance Rasopathy 2020-09-08 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 130 of the KRAS protein (p.Ala130Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs730880473, ExAC 0.004%). This variant has not been reported in the literature in individuals with KRAS-related conditions. ClinVar contains an entry for this variant (Variation ID: 180861). 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. 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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