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 label mismatch: NRAS vs undefined
  • 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_002524.5(NRAS):c.179G>A (p.Gly60Glu)

CA257021

13903 (ClinVar)

Gene: NRAS
Condition: RASopathy
Inheritance Mode: Autosomal dominant inheritance
UUID: cffb0020-8c7d-4a0c-a07f-2717d7077130
Approved on: 2024-12-03
Published on: 2025-03-26

HGVS expressions

NM_002524.5:c.179G>A
NM_002524.5(NRAS):c.179G>A (p.Gly60Glu)
NC_000001.11:g.114713911C>T
CM000663.2:g.114713911C>T
NC_000001.10:g.115256532C>T
CM000663.1:g.115256532C>T
NC_000001.9:g.115058055C>T
NG_007572.1:g.7984G>A
ENST00000369535.5:c.179G>A
ENST00000369535.4:c.179G>A
NM_002524.4:c.179G>A
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Pathogenic

Met criteria codes 5
PS4 PS3_Moderate PP1 PP3 PS2_Very Strong
Not Met criteria codes 4
PM2 BA1 BS1 BP4

Evidence Links 0

Expert Panel

Criteria Specification Information

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

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
RASopathy VCEP
The NM_002524.5:c.179G>A variant in NRAS is a missense variant predicted to cause substitution of glycine by glutamic acid at amino acid 60 (p.Gly60Glu). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00006482 (1/15428 alleles) in the European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). The computational predictor REVEL gives a score of 0.958, which is above the threshold of 0.7, evidence that correlates with impact to NRAS function (PP3). This variant has been reported in 13 probands with RASopathy (PS4; PMIDs: 19966803, 26467218, 28594414, SCV000208921.11, GeneDx, Hôpital Universitaire Robert Debré). This variant has been identified as a de novo occurrence with confirmed parental relationships in 4 individuals and as a de novo occurrence with unconfirmed parental relationships in 2 individuals with RASopathy (PS2_VeryStrong; PMIDs: 19966803 and 28594414, SCV000208921.11, GeneDx, Hôpital Universitaire Robert Debré). The variant has been reported to segregate with RASopathy in 5 affected family members from 3 family(ies (PP1; PMIDs: 19966803, 26467218, 28594414). MEK and ERK activation in COS-7 cells showed increased phophorylation indicating that this variant impacts protein function (PMID: 19966803)(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, PS4, PS3_Moderate, PM2_Supporting, PP1, PP3. (ClinGen RASopathy VCEP specifications version 2.3; 12/3/2024)
Met criteria codes
PS4
This variant has been reported in 13 probands with RASopathy (PS4; PMIDs: 19966803, 26467218, 28594414, SCV000208921.11, GeneDx, Hôpital Universitaire Robert Debré)
PS3_Moderate
MEK and ERK activation in COS-7 cells showed increased phophorylation indicating that this variant impacts protein function (PMID: 19966803)(PS3_Moderate).
PP1
The variant has been reported to segregate with RASopathy in 5 affected family members from 3 family(ies (PP1; PMIDs: 19966803, 26467218, 28594414).
PP3
The computational predictor REVEL gives a score of 0.958, which is above the threshold of 0.7, evidence that correlates with impact to NRAS function (PP3).
PS2_Very Strong
This variant has been identified as a de novo occurrence with confirmed parental relationships in 4 individuals and as a de novo occurrence with unconfirmed parental relationships in 2 individuals with RASopathy (PS2_VeryStrong; PMIDs: 19966803 and 28594414, SCV000208921.11, GeneDx, Hôpital Universitaire Robert Debré).
Not Met criteria codes
PM2
The highest population minor allele frequency in gnomAD v2.1.1 is 0.00006482 (1/15428 alleles) in the European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met).
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
BP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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