Submissions for variant NM_005343.4(HRAS):c.506G>A (p.Arg169Gln)

gnomAD frequency: 0.00007  dbSNP: rs142218590

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000505776	SCV000207863	uncertain significance	not provided	2017-06-05	criteria provided, single submitter	clinical testing	The R169Q variant has not been published in association with the Noonan syndrome spectrum to our knowledge; the variant has been observed as a germline variant in an individual with lung cancer but no reported other phenotype (Marks et al., 2007). It was observed to co-occur with the M269T pathogenic variant in the SOS1 gene in a patient at GeneDx. The variant is observed in 1/10172 (0.01%) alleles from individuals of African background in the ExAC dataset (Lek et al., 2016). R169Q 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; however, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. In summary, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae	RCV000463046	SCV000550344	uncertain significance	Costello syndrome	2023-10-14	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 169 of the HRAS protein (p.Arg169Gln). This variant is present in population databases (rs142218590, gnomAD 0.01%). This missense change has been observed in individual(s) with an unspecified cancer (PMID: 25742471). ClinVar contains an entry for this variant (Variation ID: 180856). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is not expected to disrupt HRAS function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Baylor Genetics	RCV000463046	SCV001481324	uncertain significance	Costello syndrome	2019-07-31	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Sema4, Sema4	RCV002258816	SCV002537986	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-10	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV002492617	SCV002800805	uncertain significance	Large congenital melanocytic nevus; Linear nevus sebaceous syndrome; Malignant tumor of urinary bladder; Costello syndrome; Epidermal nevus; Thyroid cancer, nonmedullary, 2	2021-09-28	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003390855	SCV004119909	uncertain significance	HRAS-related condition	2023-02-16	criteria provided, single submitter	clinical testing	The HRAS c.506G>A variant is predicted to result in the amino acid substitution p.Arg169Gln. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.016% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-532700-C-T) and is interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/180856/). Although we suspect this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.