Submissions for variant NM_005343.4(HRAS):c.64C>A (p.Gln22Lys)

dbSNP: rs121917757

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000157915	SCV000207850	likely pathogenic	not provided	2015-12-04	criteria provided, single submitter	clinical testing	The Q22K variant in the HRAS gene has been reported previously in a 13-month-old male with mild transient hypertrophic cardiomyopathy, generalized hypotonia and delayed motor development, excess of muscle spindles, fiber atrophy, postnatal transitory respiratory insufficiency, and poor sucking along with other Noonan-like features (van der Burgt et al., 2007). This variant was reported to have occurred de novo in this individual (van der Burgt et al., 2007). Subsequently, the Q22K variant was reported as a de novo variant in a 3-month-old male with dysmorphic features, a severe fatal manifestation of hypertrophic cardiomyopathy and hyperinsulinemic hypoglycemia (Sheffield et al., 2015). The Q22K 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. The Q22K variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, missense variants in nearby residues (G12S, G12C, G12D, G12V, G12A, G13C, G13D) have been reported in the Human Gene Mutation Database in association with Costello syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein.Therefore, this variant is likely pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000143898	SCV000967707	likely pathogenic	Costello syndrome	2018-12-06	criteria provided, single submitter	clinical testing	The p.Gln22Lys variant in HRAS has been reported as de novo in 1 infant with cli nical features of Costello syndrome (Sheffield 2015) and as a de novo variant in 1 toddler with congenital myopathy, transient HCM, hypotonia, low-set ears, and a triangular mouth (van der Burgt 2007). This variant has also been reported in ClinVar (Variation ID# 12609) and was absent from large population databases. C omputational prediction tools and conservation analysis suggest that the p.Gln22 Lys variant may impact the protein, though this information is not predictive en ough to determine pathogenicity. In summary, although additional studies are req uired to fully establish its clinical significance, the p.Gln22Lys variant is li kely pathogenic. ACMG/AMP Criteria applied: PM2, PM6, PP3, PP2.
Neuberg Centre For Genomic Medicine, NCGM	RCV000143898	SCV005073938	likely pathogenic	Costello syndrome		criteria provided, single submitter	clinical testing	The observed missense c.64C>A (p.Gln22Lys) variant in HRAS gene has been reported in individuals affected with HRAS-related disorders (van der Burgt et al., 2007; Sheffield et al., 2015). This variant is absent in gnomAD Exomes. This variant has been submitted to the ClinVar database as Pathogenic / Likely Pathogenic. The amino acid change p.Gln22Lys in HRAS is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Gln at position 22 is changed to a Lys changing protein sequence and it might alter its composition and physico-chemical properties. However, additional functional studies will be required to prove the pathogenicity of this variant. For these reasons, this variant has been classified as Likely Pathogenic.
OMIM	RCV000013443	SCV000033690	pathogenic	Myopathy, congenital, with excess of muscle spindles	2007-07-01	no assertion criteria provided	literature only
Blueprint Genetics	RCV000143898	SCV000188768	likely pathogenic	Costello syndrome	2013-08-28	no assertion criteria provided	clinical testing