ClinVar Miner

Submissions for variant NM_005343.4(HRAS):c.175G>A (p.Ala59Thr) (rs727503093)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen RASopathy Variant Curation Expert Panel RCV000150835 SCV000616399 likely pathogenic Costello syndrome 2017-04-03 reviewed by expert panel curation The c.175G>A (p.Ala59Thr) variant has been identified in at least 2 independent occurrences in patients with a RASopathy (PS4_Supporting; GeneDx, Partners LMM internal data; GTR ID's: 26957, 21766; ClinVar SCV000198374; SCV000207851). The p.Ala59Thr variant in HRAS has been reported in the literature to segregate with clinical features of a RASopathy in at least 3 family members (PP1; SCV000198374). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). 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). Computational prediction tools and conservation analysis suggest that the p.Ala59Thr variant may impact the protein (PP3). The variant is located in the HRAS gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). In summary, this variant meets criteria to be classified as likely pathogenic for RASopathies in an autosomal dominant manner. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PP1, PP2, PP3, PS4_Supporting, PM1, PM2.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000150834 SCV000198373 likely pathogenic Non-small cell lung cancer 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,Partners HealthCare 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.
Invitae RCV000150835 SCV000950586 uncertain significance Costello syndrome 2018-10-22 criteria provided, single submitter clinical testing 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. This variant is not present in population databases (ExAC no frequency). 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.

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