Submissions for variant NM_005343.4(HRAS):c.350A>G (p.Lys117Arg)

dbSNP: rs104894227

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen RASopathy Variant Curation Expert Panel	RCV000013439	SCV000616366	pathogenic	Costello syndrome	2017-04-03	reviewed by expert panel	curation	The c.350A>G (p.Lys117Arg) variant in HRAS has been reported in the literature in at least 2 unconfirmed de novo occurrences in patients with clinical features of a RASopathy (PM6_Strong; PMID 16443854, 16155195). In vitro functional studies provide some evidence that the p.Lys117Arg variant may impact protein function (PS3; PMID 17979197, 21850009). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of HRAS (PM1; PMID 29493581). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). Computational prediction tools and conservation analysis suggest that the p.Lys117Arg variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. ACMG/AMP criteria applied: PM6_Strong, PS3, PM1, PM2, PP3.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000013439	SCV000062133	pathogenic	Costello syndrome	2012-07-09	criteria provided, single submitter	clinical testing	The Lys117Arg variant has been reported as a de novo variant in 2 individuals wi th clinical features of Costello syndrome (Kerr 2006, Denayer 2008). Functional analyses have shown this variant to activate HRAS (Denayer 2008), and is associa ted with a milder Costello phenotype (Niihori 2011). This variant has been annot ated as a pathogenic allele in the ClinVar database (dbSNP rs104894227) and is d iscussed in the Online Mendelian Inheritance in Man (MIM#190020.0006). In summar y, this variant meets our criteria for a pathogenic variant.
GeneDx	RCV000353386	SCV000329771	pathogenic	not provided	2022-04-08	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect as this variant causes constitutive activation of the RAS/MAPK pathway and impairs GTP hydrolysis (Denayer et al., 2008; Wey et al., 2013); Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24224811, 21850009, 23093928, 16155195, 24803665, 16443854, 17979197, 32313153)
Kids Research, The Children's Hospital at Westmead	RCV000013439	SCV001244749	pathogenic	Costello syndrome		criteria provided, single submitter	research
OMIM	RCV000013439	SCV000033686	pathogenic	Costello syndrome	2008-02-01	no assertion criteria provided	literature only