Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Laboratory for Molecular Medicine, |
RCV000039811 | SCV000063500 | likely benign | not specified | 2013-11-07 | criteria provided, single submitter | clinical testing | Cys180X in exon 5 of KRAS: This variant is not expected to have clinical signifi cance because it has been previously identified by our laboratory in one individ ual who does not have clinical features of Noonan spectrum disorders and a secon d individual who is affected but carries a pathogenic variant in another gene wh ich is likely responsible for the disease. In addition, variants associated with Noonan spectrum disorders are typically gain-of-function; therefore, nonsense v ariants such as this are not common. Furthermore, this variant is located in an exon which is alternatively spliced in one isoform of KRAS. No pathogenic sequen ce variants in this region of the gene have been previously described. This vari ant has also been identified in 0.01% (1/8598) of European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP r s373169526). In summary, this variant is likely benign. |
Gene |
RCV001719761 | SCV000207886 | likely benign | not provided | 2016-10-31 | criteria provided, single submitter | clinical testing | This variant is associated with the following publications: (PMID: 26122175, 29625052, 26689913) |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000039811 | SCV000919562 | benign | not specified | 2018-07-02 | criteria provided, single submitter | clinical testing | Variant summary: KRAS c.540T>A (p.Cys180X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay. However, gain-of-function is the established molecular mechanism for disease for KRAS variants associated with Noonan spectrum disorders. The variant allele was found at a frequency of 7.9e-05 in 276946 control chromosomes (gnomAD). The observed variant frequency is approximately 6-fold higher than the estimated maximal expected allele frequency for a pathogenic variant in KRAS causing Noonan Syndrome and Related Conditions phenotype (1.3e-05), strongly suggesting that the variant is benign. The variant, c.540T>A, has been reported in the literature in an individual presenting with obesity, webbed neck, acne, bilateral inguinal hernia repair, abnormal pubertal development (Bhoj_2016) and an individual presenting with constrictive pericarditis (Herkert_2018) in whom it was classified as "Likely Benign" and "VUS" respectively. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as uncertain significance. Another ClinVar submission from a clinical diagnostic laboratory (evaluation before 2014) indicate the variant co-occurred with another pathogenic variant in a different gene and the laboratory classified the variant as "likely benign." Based on the evidence outlined above, the variant was classified as benign. |
St. |
RCV001526812 | SCV001737457 | uncertain significance | Cardio-facio-cutaneous syndrome | 2021-03-29 | criteria provided, single submitter | clinical testing | The KRAS c.540T>A (p.Cys180X) change is a nonsense variant in an alternate transcript of the KRAS gene that is predicted to cause protein truncation. The disease mechanism for RASopathies is gain-of-function caused by missense changes and protein truncating variants do not have an established correlation to disease (BP1). This variant has a maximum subpopulation frequency of 0.015% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/12-25368405-A-T?dataset=gnomad_r2_1). This is neither rare or greater than expected for the disorder based on thresholds defined by the ClinGen RASopathy Variant Curation Expert Panel (PMID:29493581). This variant has been reported in an individual with constrictive pericarditis (PMID: 29517769), as well as individuals who do not present with clinical features of RASopathy disorders (PMID: 27763634, internal data). Data deposited into ClinVar indicates that this variant was identified in an individual who is affected by carries a pathogenic variant in another gene which is likely responsible for the disease (ClinVar Accession: SCV000063500.5). In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria, as specified by the ClinGen RASopathy Variant Curation Expert Panel: BP1. |