3-138372951-G-T

Position:

• chr3-138372951-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 11 ACMG points: 11P and 0B. PP3 PS3_Moderate PS4_Supporting PM2_Supporting PM1 PS2

This summary comes from the ClinGen Evidence Repository: The c.68G>T (p.Gly23Val) variant in MRAS is a missense variant predicted to cause substitution of glycine by valine at amino acid 23. This variant has a minor allele frequency of 0.00008624% (1/1159522) in the European (non-Finnish) population in gnomAD v4 (PM2_Supporting). The computational predictor REVEL gives a score of 0.923, which is above the threshold of 0.7, evidence that correlates with impact to MRAS function (PP3). This variant resides within the P-loop (amino acids 20 – 27) of MRAS that is defined as a critical functional domain by the ClinGen RASopathy VCEP (PM1). This variant has been identified in 1 individual with features of RASopathy (PS4_Supporting; PMID:28289718). This variant has been identified as a de novo occurrence with confirmed parental relationships in 1 individual with features of RASopathy (PS2; PMID:28289718). RAS and ERK activation assays in HEK293T/17 showed constitutively active forms of MRAS indicating that this variant impacts protein function (PMID:28289718) (PS3_Moderate). Given the Moderate strength of gene-disease relationship between MRAS and autosomal dominant RASopathy, ClinGen’s sequence variant interpretation working group does not recommend the classification of variants in this gene beyond likely pathogenic. Based on ACMG/AMP criteria alone, this variant has enough supporting evidence to be classified as pathogenic; however, the RASopathy VCEP has downgraded this classification to likely pathogenic based on ClinGen policy. In summary, this variant currently meets the criteria to be classified as likely pathogenic for autosomal dominant RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: PS2, PS3_M, PM1, PS4_P, PM2_P, PP3. (RASopathy VCEP specifications version 1.1; 9/17/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA354671596/MONDO:0021060/087

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: MRAS NM_001085049.3 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:7
• Conservation: PhyloP100: 9.92

Genes affected

MRAS (HGNC:7227): (muscle RAS oncogene homolog) This gene encodes a member of the Ras family of small GTPases. These membrane-associated proteins function as signal transducers in multiple processes including cell growth and differentiation, and dysregulation of Ras signaling has been associated with many types of cancer. The encoded protein may play a role in the tumor necrosis factor-alpha and MAP kinase signaling pathways. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Nov 2011]

ACMG classification

Verdict is Likely_pathogenic. Variant got 11 ACMG points.

• PS2: For more information check the summary or visit ClinGen Evidence Repository.
• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MRAS	NM_001085049.3	c.68G>T	p.Gly23Val	missense_variant	2/6	ENST00000423968.7	NP_001078518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MRAS	ENST00000423968.7	c.68G>T	p.Gly23Val	missense_variant	2/6	1	NM_001085049.3	ENSP00000389682	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.08e-7 AC: 1 AN: 1412440 Hom.: 0 Cov.: 33 AF XY: 0.00000143 AC XY: 1 AN XY: 701546

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.16e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:7

Revision: reviewed by expert panel

Submissions by phenotype

Noonan syndrome 11 Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins-Biomnis	Nov 03, 2022	- -
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	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	May 20, 2023	The observed missense variant c.68G>T(p.Gly23Val) in MRAS gene has been reported previously in individual(s) with Noonan syndrome. A different missense change at the same codon (p.Gly23Arg) has been reported to be associated with MRAS related disorder. Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (Motta M, et al., 2020; Higgins EM, et al., 2019). This variant is absent in the gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic. The amino acid Glycine at position 23 is changed to a Valine changing protein sequence and it might alter its composition and physico-chemical properties. Multiple lines of computational evidence (Polyphen - Possibly damaging, SIFT – Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The residue is conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -

RASopathy Pathogenic:2

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. -
Likely pathogenic, reviewed by expert panel	curation	ClinGen RASopathy Variant Curation Expert Panel	Sep 17, 2024	The c.68G>T (p.Gly23Val) variant in MRAS is a missense variant predicted to cause substitution of glycine by valine at amino acid 23. This variant has a minor allele frequency of 0.00008624% (1/1159522) in the European (non-Finnish) population in gnomAD v4 (PM2_Supporting). The computational predictor REVEL gives a score of 0.923, which is above the threshold of 0.7, evidence that correlates with impact to MRAS function (PP3). This variant resides within the P-loop (amino acids 20 – 27) of MRAS that is defined as a critical functional domain by the ClinGen RASopathy VCEP (PM1). This variant has been identified in 1 individual with features of RASopathy (PS4_Supporting; PMID:28289718). This variant has been identified as a de novo occurrence with confirmed parental relationships in 1 individual with features of RASopathy (PS2; PMID:28289718). RAS and ERK activation assays in HEK293T/17 showed constitutively active forms of MRAS indicating that this variant impacts protein function (PMID:28289718) (PS3_Moderate). Given the Moderate strength of gene-disease relationship between MRAS and autosomal dominant RASopathy, ClinGen’s sequence variant interpretation working group does not recommend the classification of variants in this gene beyond likely pathogenic. Based on ACMG/AMP criteria alone, this variant has enough supporting evidence to be classified as pathogenic; however, the RASopathy VCEP has downgraded this classification to likely pathogenic based on ClinGen policy. In summary, this variant currently meets the criteria to be classified as likely pathogenic for autosomal dominant RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: PS2, PS3_M, PM1, PS4_P, PM2_P, PP3. (RASopathy VCEP specifications version 1.1; 9/17/2024) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D;D;T;D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	.;.;D;D
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Pathogenic	3.6	H;H;.;H
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-8.2	D;D;D;D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;D;.;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;D;.;D
Vest4		0.91
MutPred		0.92		Loss of ubiquitination at K26 (P = 0.0615);Loss of ubiquitination at K26 (P = 0.0615);Loss of ubiquitination at K26 (P = 0.0615);Loss of ubiquitination at K26 (P = 0.0615);
MVP		0.95
MPC		2.5
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.97
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1576359216; hg19: chr3-138091793;