Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_002524.5(NRAS):c.360G>A (p.Leu120=)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA134569

40476 (ClinVar)

Gene: NRAS

Condition: RASopathy

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: d558c042-a22e-493d-9b5b-4a98819adf41

Approved on: 2024-09-17

Published on: 2024-10-31

HGVS expressions

NM_002524.5:c.360G>A

NM_002524.5(NRAS):c.360G>A (p.Leu120=)

NC_000001.11:g.114709659C>T

CM000663.2:g.114709659C>T

NC_000001.10:g.115252280C>T

CM000663.1:g.115252280C>T

NC_000001.9:g.115053803C>T

NG_007572.1:g.12236G>A

ENST00000369535.5:c.360G>A

ENST00000369535.4:c.360G>A

NM_002524.4:c.360G>A

Likely Benign

BS1 BP4 BP7 BP5

BA1 PP3 PM2

Evidence Links 0

Expert Panel

RASopathy VCEP

Criteria Specification Information

Criteria Specification: ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for NRAS Version 2.1.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

RASopathy VCEP

The NM_002524.5:c.360G>A (p.Leu120=) variant is a synonymous (silent) variant in NRAS that is not predicted by SpliceAI to impact splicing. In addition, it occurs at a nucleotide that is not conserved as shown by UCSC Genome Browser (BP4, BP7). The filtering allele frequency (the lower threshold of the 95% CI of 77/129188) of the c.360G>A variant in NRAS is 0.0004832 for European (non-Finnish) chromosomes by gnomAD v2.1.1, which is higher than the ClinGen RASopathy VCEP threshold (≥0.00025) for BS1, and therefore meets this criterion (BS1). Observed in 1 individual with a co-occurring likely pathogenic/pathogenic variant in a gene that explains their condition, Noonan syndrome (Invitae internal data, ClinVar SCV000253394.6). In summary, this variant meets the criteria to be classified as likely benign for autosomal dominant RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: BS1, BP4, BP5, BP7. (ClinGen RASopathy VCEP specifications version 2.1; 9/17/2024)

BS1

The filtering allele frequency (the lower threshold of the 95% CI of 77/129188) of the c.360G>A variant in NRAS is 0.0004832 for European (non-Finnish) chromosomes by gnomAD v2.1.1, which is higher than the ClinGen RASopathy VCEP threshold (≥0.00025) for BS1, and therefore meets this criterion (BS1).

BP4

The c.360G>A (p.Leu120=) variant is a synonymous (silent) variant that is not predicted by SpliceAI to impact splicing. In addition, it occurs at a nucleotide that is not conserved as shown by UCSC Genome Browser (BP4, BP7).

BP7

BP5

Observed in 1 individual with a co-occurring likely pathogenic/pathogenic variant in a gene that explains their condition, Noonan syndrome (Invitae internal data, ClinVar SCV000253394.6).

BA1

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PP3

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PM2

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

Curation History

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