ClinVar Miner

Submissions for variant NM_012250.6(RRAS2):c.208G>A (p.Ala70Thr)

gnomAD frequency: 0.00001  dbSNP: rs782457908
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen RASopathy Variant Curation Expert Panel RCV004760768 SCV005367986 likely pathogenic RASopathy 2024-09-17 reviewed by expert panel curation The c.208G>A (p.Ala70Thr) variant in RRAS2 is a missense variant predicted to cause substitution of alanine by threonine at amino acid 70. The highest population filtering allele frequency in gnomAD v2.1.1 is 0.00001084 (2/30538 alleles) in the South Asian population (PM2_Supporting, BS1, and BA1 are not met). The computational predictor REVEL gives a score of 0.863, which is above the threshold of 0.7, evidence that correlates with impact to RRAS2 function (PP3). This variant resides within the Switch II domain (amino acids 68 – 75), of RRAS2 that is defined as a critical functional domain by the ClinGen RASopathy VCEP (PM1). ERK Activation in HEK293T cells showed constitutive promotion of increased ERK phosphorylation indicating that this variant impacts protein function (PMID:31130282)(PS3_Supporting). This variant has been reported in 2 probands with features of RASopathy (PS4_Supporting; PMID:31130282). This variant has been identified as a de novo occurrence with confirmed parental relationships in 1 individual with features of RASopathy (PS2; PMID:31130282). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: PS2, PM1, PS3_Supporting, PS4_Supporting, PP3. (RASopathy VCEP specifications version 1.1; 9/17/2024)
Tartaglia Lab, Genetics and Rare Diseases Research Division, Bambino Gesu' Children's Hospital RCV000852397 SCV000902251 pathogenic Noonan syndrome 2019-04-01 criteria provided, single submitter research this is a pathogenic variant associated with Noonan Syndrome
PreventionGenetics, part of Exact Sciences RCV003411705 SCV004115267 uncertain significance RRAS2-related disorder 2023-02-20 criteria provided, single submitter clinical testing The RRAS2 c.208G>A variant is predicted to result in the amino acid substitution p.Ala70Thr. This variant was reported to segregate with disease in a three generation family with Noonan syndrome (Capri et al. 2019. PubMed ID: 31130282). Functional studies demonstrate this variant results in increased p-MEK/ERK levels, consistent with a gain-of-function mechanism, resulting in hyperactivation of the RAS pathway (Capri et al. 2019. PubMed ID: 31130282). This variant is reported in 0.0065% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-14316397-C-T). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Institute of Human Genetics, University of Leipzig Medical Center RCV000853183 SCV005397117 likely pathogenic Noonan syndrome 12 2024-10-30 criteria provided, single submitter clinical testing Criteria applied: PS2,PM1,PS3_SUP,PS4_SUP,PP3
OMIM RCV000853183 SCV000995987 pathogenic Noonan syndrome 12 2019-10-15 no assertion criteria provided literature only

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