Submissions for variant NM_001085049.3(MRAS):c.68G>T (p.Gly23Val)

dbSNP: rs1576359216

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Baylor Genetics	RCV000787303	SCV001522083	pathogenic	Noonan syndrome 11	2020-06-18	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
3billion	RCV000787303	SCV003841392	pathogenic	Noonan syndrome 11	2023-02-23	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 28289718). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.92; 3Cnet: 0.84). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000635781). A different missense change at the same codon (p.Gly23Arg) has been reported to be associated with MRAS related disorder (ClinVar ID: VCV000560681 / PMID: 31108500). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003155311	SCV003844428	pathogenic	RASopathy	2023-02-07	criteria provided, single submitter	clinical testing	Variant summary: MRAS c.68G>T (p.Gly23Val) results in a non-conservative amino acid change located in the small GTP-binding protein domain (IPR005225) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 208010 control chromosomes (gnomAD). c.68G>T has been reported in the literature as a de novo occurrence in an individual affected with Noonan Syndrome with Cardiac Hypertrophy (Higgins_2017). This suggests that the variant is likely associated with disease. Several publications report experimental evidence evaluating an impact on protein function and found that the variant results in a gain of function (e.g. Higgins_2017, Motta_2020). The variant causes an overactivation of the RAS/MAPK pathway with up to 40-fold more GTP loading than WT MRAS after stimulation with EGF, indicating that the variant protein is constituatively active (Higgins_2017). Additionally, the variant was found to elicit a cardiac hypertrophy phenotype in iPSC-derived cardiomyocytes that includes increased cell size, changes in cardiac gene expression, and abnormal calcium handling (Higgins_2019). Two submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and both classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Eurofins-Biomnis	RCV000787303	SCV003935069	pathogenic	Noonan syndrome 11	2022-11-03	criteria provided, single submitter	clinical testing
OMIM	RCV000787303	SCV000926240	pathogenic	Noonan syndrome 11	2019-07-11	no assertion criteria provided	literature only