Submissions for variant NM_005343.4(HRAS):c.35G>C (p.Gly12Ala)

dbSNP: rs104894230

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000207503	SCV000207845	pathogenic	not provided	2024-09-24	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect caused by increased phosphorylation of ERK, suggesting an activation of the RAS/MAPK pathway (Denayer et al., 2008; Niihori et al., 2011); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 17979197, 28027064, 17601930, 30055033, 34845155, 24224811, 21686750, 22317973, 23093928, 16170316, 19035362, 24803665, 27589201, 24169525, 16835863, 30762279, 30885829, 31394527, 31560489, 33482860, 33224014, 37488489, 33057194, 35982159, 34643321, 21850009)
Molecular Diagnostics Lab, Nemours Children's Health, Delaware	RCV000207503	SCV000263054	pathogenic	not provided	2014-06-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000013437	SCV000698555	pathogenic	Costello syndrome	2017-07-17	criteria provided, single submitter	clinical testing	Variant summary: The HRAS c.35G>C (p.Gly12Ala) variant involves the alteration of a conserved nucleotide. 3/3 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). Functional studies showed that this variant increased RAS pathway activation in NIH 3T3 cells (Niihori_JHG_2011) and increased proliferation in Ba/F3 cells (Denayer_HM_2008). The variant of interest has not been found in a large, broad control population, ExAC in 120014 control chromosomes. This variant was reported in multiple Costello syndrome patients, including de novo occurrences (Aoki_NatGen_2005, Robbins_AJMG_2016, Niihori_JHG_2011). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Ambry Genetics	RCV000623953	SCV000741342	pathogenic	Inborn genetic diseases	2016-03-03	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000762848	SCV000893208	pathogenic	Large congenital melanocytic nevus; Linear nevus sebaceous syndrome; Malignant tumor of urinary bladder; Costello syndrome; Epidermal nevus; Thyroid cancer, nonmedullary, 2	2018-10-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000013437	SCV000956118	pathogenic	Costello syndrome	2023-04-21	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly12 amino acid residue in HRAS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16170316, 20979192, 21834037, 21850009, 22317973, 23751039). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects HRAS function (PMID: 17979197, 21850009, 24224811). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt HRAS function. ClinVar contains an entry for this variant (Variation ID: 12603). This missense change has been observed in individual(s) with Costello syndrome (PMID: 16170316, 16372351, 16443854, 16835863, 17601930, 18042262, 21850009, 22420426, 28027064). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 12 of the HRAS protein (p.Gly12Ala).
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001813186	SCV002060961	pathogenic	Noonan syndrome and Noonan-related syndrome	2021-04-06	criteria provided, single submitter	clinical testing
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000013437	SCV005091973	pathogenic	Costello syndrome	2024-07-22	criteria provided, single submitter	clinical testing	This variant was found de novo in a child with Costello syndrome. It disrupts the p.Gly12 amino acid residue in HRAS. Other variants that disrupt this residue have been determined to be pathogenic (PMID: 16170316, 20979192, 21834037, 21850009, 22317973, 23751039). Experimental studies have shown that this missense change affects HRAS function (PMID: 17979197, 21850009, 24224811). In silico prediction indicates that this missense variant is expected to disrupt HRAS function. This missense change has been observed in individuals with Costello syndrome (PMID: 16170316, 16372351, 16443854, 16835863, 17601930, 18042262, 21850009, 22420426, 28027064). For these reasons, this variant has been classified as Pathogenic.
OMIM	RCV000013437	SCV000033684	pathogenic	Costello syndrome	2005-10-01	no assertion criteria provided	literature only
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV001257536	SCV001434362	pathogenic	Rhabdomyosarcoma	2020-09-01	no assertion criteria provided	provider interpretation