Submissions for variant NM_005343.4(HRAS):c.175G>A (p.Ala59Thr)

dbSNP: rs727503093

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen RASopathy Variant Curation Expert Panel	RCV004760350	SCV000616399	likely pathogenic	RASopathy	2024-09-17	reviewed by expert panel	curation	The c.175G>A variant in the HRAS gene is a missense variant predicted to cause substitution of alanine by threonine at amino acid 59 (p.Ala59Thr). This variant was absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.755 supporting deleterious impact to HRAS function (PP3). This variant resides within a region (amino acids 57 – 64), of HRAS that is defined as a critical functional domain by the ClinGen RASopathy VCEP (PM1). The c.175G>A (p.Ala59Thr) variant has been identified in at least 3 independent occurrences in patients with a RASopathy (PS4_Moderate; GeneDx, Partners Laboratory for Molecular Medicine, Invitae internal data, ClinVar SCV000198374.4, SCV000950586.1). Moreover, this variant has been reported to segregate with clinical features of a RASopathy in at least 3 family members (PP1; Partners Laboratory for Molecular Medicine internal data, ClinVar SCV000198374.4). In summary, this variant meets criteria to be classified as likely pathogenic for autosomal dominant RASopathies based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: PS4_Moderate, PM1, PM2_Supporting, PP1, PP3 (Specification Version 2.1, 09/17/2024)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000150834	SCV000198373	likely pathogenic	Non-small cell lung carcinoma	2017-12-07	criteria provided, single submitter	clinical testing	This variant has been reported in the literature as a variant occurring in retro viral ras oncogenes, and has been demonstrated to have transforming activity in some in vitro studies (Barbacid 1987, Tsuchida 1982, Dhar 1982, Lacai 1986). Ala 59 is also highly conserved among distantly related species.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000150835	SCV000198374	likely pathogenic	Costello syndrome	2017-12-07	criteria provided, single submitter	clinical testing	The p.Ala59Thr variant in HRAS has been identified by our laboratory in three af fected relatives with clinical features of a RASopathy disorder. It was absent f rom large population studies. The p.Ala59Thr variant is known to occur in retrov iral ras oncogenes and has been demonstrated to have transforming activity in mu ltiple in vitro studies (Dhar 1982, Tsuchida 1982, Lacal 1986, Barbacid 1987). C omputational prediction tools and conservation analysis support that the variant may impact the protein. However, these in vitro assays and computational analys es may not accurately represent biological function. In addition, our laboratory has identified a different variant associated with RASopathies at the same posi tion (p.Ala59Leu), which suggests that changes to this position are not tolerate d. In summary, although additional studies are required to fully establish its c linical significance, the p.Ala59Thr variant is likely pathogenic. ACMG/AMP Crit eria applied: PM2, PP2, PP3, PS3_Supporting, PS4_Supporting.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000150835	SCV000950586	uncertain significance	Costello syndrome	2018-10-18	criteria provided, single submitter	clinical testing	This variant has not been reported in the literature in individuals with HRAS-related disease. ClinVar contains an entry for this variant (Variation ID: 40435). Experimental studies have shown that this missense change results in elevated GTP nucleotide exchange rate in cultured cells (PMID: 3540608, 3004741). 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. This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with threonine at codon 59 of the HRAS protein (p.Ala59Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine.
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000150835	SCV001448800	likely pathogenic	Costello syndrome	2016-11-23	criteria provided, single submitter	clinical testing