ClinVar Miner

Submissions for variant NM_005343.4(HRAS):c.181C>A (p.Gln61Lys) (rs28933406)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000587258 SCV000698552 likely pathogenic Noonan syndrome 3 2017-08-28 criteria provided, single submitter clinical testing Variant summary: The HRAS c.181C>A (p.Gln61Lys) variant involves the alteration of a conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant is absent in 120996 control chromosomes. This variant has been reported as somatic variant in many cancer samples and has been shown to strongly activate the transforming potential of HRAS gene and produce an 8-10 fold reduction in GTPase activity by functional study (Der_1986). This supports the role of inhibition of GTP hydrolysis resulting in a constitutively activated HRAS protein, consistent with the established mechanism of disease attributed to variants in the HRAS gene. In addition, codon Gln61 has been reported as a hotspot for transforming mutations (Saxowsky_2008), and variant was reported as a somatic variant by Database of Curated Mutations (DoCM) to Likely pathogenic. This variant has not, to our knowledge, been reported as a germline variant in patients with Noonan syndrome and related conditions. Taken together, this variant is classified as likely pathogenic until more evidence becomes available.
GeneDx RCV000681435 SCV000808898 pathogenic not provided 2018-08-16 criteria provided, single submitter clinical testing The Q61K missense variant in the HRAS gene has not been previously published as a germline variant in association with RASopathies. However, the Q61K variant is not observed in large population cohorts (Lek et al., 2016). The variant is a semi-conservative amino acid substitution in the GTP nucleotide binding region, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Missense variants in the same (Q61R) and nearby residues (T58I, G60D/V, E63K) of HRAS have been reported in the Human Gene Mutation Database in association with Noonan spectrum disorders (Stenson et al., 2014). Additionally, variants at the same codon in KRAS (Q61P) and NRAS (Q61P/H/R) have been reported, supporting the functional importance of this region of the protein. We interpret this variant as pathogenic
OMIM RCV000013434 SCV000033681 pathogenic Thyroid cancer, nonmedullary, 2 2009-11-01 no assertion criteria provided literature only
OMIM RCV000022795 SCV000044084 pathogenic Spermatocytic seminoma 2009-11-01 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000439343 SCV000505660 likely pathogenic Breast neoplasm 2015-07-14 no assertion criteria provided literature only
Institute of Medical Sciences, Banaras Hindu University RCV001255683 SCV001432248 pathogenic Lip and oral cavity carcinoma 2019-04-30 no assertion criteria provided research

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