The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computed assertion could be determined for this classification!


Variant: NM_012250.6(RRAS2):c.215A>T (p.Gln72Leu)

CA120437

9447 (ClinVar)

Gene: RRAS2
Condition: Noonan syndrome
Inheritance Mode: Autosomal dominant inheritance
UUID: bcb97244-8c08-4487-8fa4-0d4bb3925111
Approved on: 2024-09-17
Published on: 2024-10-01

HGVS expressions

NM_012250.6:c.215A>T
NM_012250.6(RRAS2):c.215A>T (p.Gln72Leu)
NC_000011.10:g.14294844T>A
CM000673.2:g.14294844T>A
NC_000011.9:g.14316390T>A
CM000673.1:g.14316390T>A
NC_000011.8:g.14272966T>A
NG_017058.1:g.74663A>T
ENST00000256196.9:c.215A>T
ENST00000256196.8:c.215A>T
ENST00000414023.6:c.-17A>T
ENST00000526063.5:c.-17A>T
ENST00000526717.1:c.*167A>T
ENST00000529237.5:c.-17A>T
ENST00000531421.5:c.-17A>T
ENST00000531807.5:c.158A>T
ENST00000532814.5:c.-17A>T
ENST00000532950.5:c.*155A>T
ENST00000534746.5:c.-17A>T
ENST00000537760.5:c.110A>T
ENST00000545643.5:c.212A>T
NM_001102669.2:c.-17A>T
NM_001177314.1:c.110A>T
NM_001177315.1:c.-17A>T
NM_012250.5:c.215A>T
NM_001177314.2:c.110A>T
More

Pathogenic

Met criteria codes 6
PS3_Moderate PP3 PM2_Supporting PM1 PS4_Supporting PS2_Very Strong
Not Met criteria codes 3
BP4 BA1 BS1

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RRAS2 Version 1.1.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
RASopathy VCEP
The c.215A>T (p.Gln72Leu) variant in RRAS2 is a missense variant predicted to cause substitution of glutamine by leucine at amino acid 72. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.918, which is above the threshold of 0.7, evidence that correlates with impact to RRAS2 function (PP3). This variant resides within the Switch II domain (amino acids 68 – 75) of RRAS2 that is defined as a critical functional domain by the ClinGen RASopathy VCEP (PM1). This variant has been reported in 2 probands with features of RASopathy (PS4_Supporting; PMID:31130285, 33686258). This variant has been identified as a de novo occurrence with confirmed parental relationships in 2 individuals with features of RASopathy (PS2_VeryStrong; PMID:31130285, 33686258). Pull-down assays with the Raf-Ras-binding domain (RBD, residues 1–149) of RAF1 in HEK293 cells showed increased binding of activated RAS indicating that this variant impacts protein function. Similar results were seen in an immunoblotting assay of the cell lysates expressing WT/variant RRAS2 using anti-phospho-MEK1/2 and phospho-ERK1/2 antibodies. Additionally, Zebrafish embryos injected with variant mRNA showed significantly increased ceratohyal angles compared to the uninjected controls (PMID:31130285)(PS3_Moderate). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: PS2_VeryStrong, PS3_Moderate, PM1, PS4_Supporting, PM2_Supporting, PP3. (RASopathy VCEP specifications version 1.1; 9/17/2024)
Met criteria codes
PS3_Moderate
Pull-down assays with the Raf-Ras-binding domain (RBD, residues 1–149) of RAF1 in HEK293 cells showed increased binding of activated RAS indicating that this variant impacts protein function (PMID:31130285)(PS3). Similar results were seen in an immunoblotting assay of the cell lysates expressing WT/variant RRAS2 using anti-phospho-MEK1/2 and phospho-ERK1/2 antibodies. Additionally, Zebrafish embryos injected with variant mRNA showed significantly increased ceratohyal angles compared to the uninjected controls.
PP3
The computational predictor REVEL gives a score of 0.918, which is above the threshold of 0.7, evidence that correlates with impact to RRAS2 function (PP3).
PM2_Supporting
This variant is absent from gnomAD v2.1.1 (PM2_Supporting).
PM1
This variant resides within the Switch II domain (amino acids 68 – 75) of RRAS2 that is defined as a critical functional domain by the ClinGen RASopathy VCEP (PM1).
PS4_Supporting
This variant has been reported in 2 probands, one with suggestive facial dysmorphology, dilated cardiomyopathy, short stature (-5.9 SD), pectus excavatum, severe ID, and cryptorchidism and a second diagnosed with Noonan syndrome (PS4_Supporting; PMID:31130285, 33686258).
PS2_Very Strong
This variant has been identified as a de novo occurrence with confirmed parental relationships in 2 individuals, one with suggestive facial dysmorphology, dilated cardiomyopathy, short stature (-5.9 SD), pectus excavatum, severe ID, and cryptorchidism and a second diagnosed with Noonan syndrome. (PS2_VeryStrong; PMID:31130285, 33686258).
Not Met criteria codes
BP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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