chr3-138372951-G-T
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong
The NM_001085049.3(MRAS):c.68G>T(p.Gly23Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000708 in 1,412,440 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G23R) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001085049.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MRAS | NM_001085049.3 | c.68G>T | p.Gly23Val | missense_variant | 2/6 | ENST00000423968.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MRAS | ENST00000423968.7 | c.68G>T | p.Gly23Val | missense_variant | 2/6 | 1 | NM_001085049.3 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 7.08e-7 AC: 1AN: 1412440Hom.: 0 Cov.: 33 AF XY: 0.00000143 AC XY: 1AN XY: 701546
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Noonan syndrome 11 Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jun 18, 2020 | This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 11, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins-Biomnis | Nov 03, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Feb 23, 2023 | 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. - |
RASopathy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 07, 2023 | 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at