Variant: NM_005343.4(HRAS):c.350A>G (p.Lys117Arg)

CA256490

12605 (ClinVar)

Gene: HRAS

Condition: RASopathy

Inheritance Mode: Autosomal dominant inheritance

UUID: 42e841f0-7121-4d9d-a2ae-ebc27adacd88

Approved on: 2024-12-03

Published on: 2025-03-31

HGVS expressions

NM_005343.4:c.350A>G
NM_005343.4(HRAS):c.350A>G (p.Lys117Arg)
NC_000011.10:g.533553T>C
CM000673.2:g.533553T>C
NC_000011.9:g.533553T>C
CM000673.1:g.533553T>C
NC_000011.8:g.523553T>C
NG_007666.1:g.6998A>G
ENST00000397594.7:c.350A>G
ENST00000417302.7:c.350A>G
ENST00000397594.6:c.68A>G
ENST00000417302.6:c.350A>G
ENST00000462734.2:c.350A>G
ENST00000311189.8:c.350A>G
ENST00000311189.7:c.350A>G
ENST00000397594.5:c.350A>G
ENST00000397596.6:c.350A>G
ENST00000417302.5:c.350A>G
ENST00000451590.5:c.350A>G
ENST00000462734.1:n.43A>G
ENST00000478324.5:n.60A>G
ENST00000479482.1:n.271A>G
ENST00000493230.5:c.350A>G
NM_001130442.1:c.350A>G
NM_005343.2:c.350A>G
NM_176795.3:c.350A>G
NM_001130442.2:c.350A>G
NM_001318054.1:c.31A>G
NM_005343.3:c.350A>G
NM_176795.4:c.350A>G
NM_001318054.2:c.31A>G
NM_001130442.3:c.350A>G
NM_176795.5:c.350A>G

Pathogenic

• Met criteria codes: PS2_Very Strong PS4_Moderate PM2_Supporting PP3 PS3_Moderate

• Not Met criteria codes: BP4 BS1 BS3 BA1

Expert Panel

RASopathy VCEP

Criteria Specification Information

Criteria Specification: ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for HRAS Version 2.3.0

Evidence submitted by expert panel

RASopathy VCEP

The c.350A>G variant in the HRAS gene is a missense variant predicted to cause substitution of lysine by arginine at amino acid 117 (p.Lys117Arg). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.916, which is above the threshold of 0.7, evidence that correlates with impact to HRAS function (PP3). At least 4 independent occurrences of this variant have been detected in patients with a RASopathy, of which 3 were reported as confirmed de novo cases while 1 was an unconfirmed de novo occurrence (PS2_VeryStrong, PS4_Moderate; PMID: 16443854, 17979197, 35595280, 32313153). In vitro functional assays showed that the variant increased RAS/MEK/ERK activation compared to wildtype (PS3_Moderate; PMID: 17979197, 21850009). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant RASopathies based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: PS2_VeryStrong, PS4_Moderate, PS3_Modertae, PM2_Supporting, PP3 (Specification Version 2.3, 12/3/2024)

Met criteria codes

• PS2_Very Strong: At least 3 cases were reported as confirmed de novo cases while 1 was an unconfirmed de novo occurrence (PMIDs: 17979197, 35595280, 32313153, 35595280)
• PS4_Moderate: At least 4 independent occurrences of this variant have been detected in patients with a RASopathy (PMIDs: 16443854, 17979197, 35595280, 32313153).
• PM2_Supporting: This variant is absent from gnomAD v2.1.1
• PP3: The computational predictor REVEL gives a score of 0.916, which is above the threshold of 0.7, evidence that correlates with impact to HRAS function
• PS3_Moderate: In vitro functional assays showed that the variant increased RAS/MEK/ERK activation compared to wildtype (PMIDs: 17979197, 21850009).

Not Met criteria codes

• BP4: The computational predictor REVEL gives a score of 0.916, which is above the threshold of 0.7, evidence that correlates with impact to HRAS function
• BS1: This variant is absent from gnomAD v2.1.1
• BS3: In vitro functional studies provide some evidence that the p.Lys117Arg variant may impact protein function (PMID 17979197, 21850009).
• BA1: This variant is absent from gnomAD v2.1.1