Variant classification summary

NM_002524.5:c.182A>G

NRAS · NP_002515.1:p.(Gln61Arg) · NM_002524.5

GRCh37: chr1:115256529 T>C · GRCh38: chr1:114713908 T>C

Gene: NRAS Transcript: NM_002524.5

Final call

Pathogenic

PS1 strong PS3 moderate PM1 moderate PM2 supporting PM5 moderate PP3 supporting

Variant details

Gene

NRAS

Transcript

NM_002524.5

Protein

NP_002515.1:p.(Gln61Arg)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_002524.5:c.182A>G (p.Gln61Arg) is a missense variant in exon 3 of NRAS affecting the critical Switch II domain (codon 61). This variant is absent from population databases (gnomAD v2.1, v4.1, gnomAD-Canada).

2

The p.Gln61Arg amino acid change is an established pathogenic variant at the analogous residue in HRAS and KRAS, satisfying PS1 at Strong strength per the RASopathy VCEP.

3

Functional studies approved by the RASopathy VCEP have characterized this variant across at least two independent assay platforms (RAS Activation, MEK Activation, ERK Activation, AKT Phosphorylation), supporting a gain-of-function mechanism consistent with RASopathy pathogenesis (PS3_Moderate).

4

The variant lies within the Switch II domain (AA 57-64), a VCEP-approved critical functional domain, satisfying PM1 at Moderate strength. Residue Q61 is the key catalytic glutamine that positions the water molecule for GTP hydrolysis.

5

Multiple alternative pathogenic residue changes at NRAS codon 61 (Q61K, Q61L, Q61H) are established in the literature, satisfying PM5 at Moderate strength per VCEP rules.

6

The variant is absent from gnomAD population databases, meeting PM2 at Supporting strength (VCEP-downgraded).

7

REVEL in silico prediction score of 0.888 exceeds the VCEP threshold of 0.7, supporting a deleterious effect (PP3).

8

Applying the RASopathy VCEP combination rules: one Strong criterion (PS1) and at least two Moderate criteria (PS3 + PM1 + PM5) satisfy Rule 7 or Rule 6 for Pathogenic classification. Alternatively, one Strong plus one Moderate plus two Supporting criteria may satisfy other rules. The evidence combination is consistent with a Pathogenic classification.

Final determination: Rule7 in the ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for NRAS Version 2.3.0 v2.3.0 criteria-combination framework is satisfied by the adjudicated criteria, so the variant is classified as Pathogenic.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	This is a missense variant (c.182A>G, p.Gln61Arg). PVS1 is applicable only to null variants (nonsense, frameshift, canonical splice sites, initiation codon, exon deletions). The RASopathy VCEP marks PVS1 as Not Applicable for NRAS missense variants.	cspec pvs1_gene_context pvs1_variant_assessment
PS1	Met	The p.Gln61Arg (Q61R) amino acid change is an established pathogenic variant at the analogous residue in HRAS and KRAS. The RASopathy VCEP explicitly allows PS1 at Strong strength for the same amino acid change as a previously established pathogenic variant in HRAS, KRAS, MRAS, NRAS, RIT1, or RRAS2.	cspec clinvar PMID:12727991
PS2	Not met	No de novo occurrence data with confirmed maternity and paternity is available for this variant in the case materials. The RASopathy VCEP requires point-based scoring with phenotypic specifications; no de novo probands were identified.	cspec
PS3	Met	The RASopathy VCEP has approved four functional assay types for NRAS: RAS Activation, MEK Activation, ERK Activation, and AKT Phosphorylation assays. The variant p.Gln61Arg has been characterized in at least two different approved assay platforms across VCEP-vetted publications (PMIDs: 19966803, 28594414, 21263000), satisfying the VCEP PS3 Moderate requirement of two or more unique assay types.	cspec vcep_svi_rasopathy_vcep_v2_approved_functional_studies
PS4	Not assessed	The RASopathy VCEP uses point-based scoring for PS4 requiring specific proband counts with RASopathy phenotypes. While this variant is reported in ClinVar as Pathogenic by 9 clinical laboratories and has a high somatic count in COSMIC (n=2170), the case materials lack germline proband counts with RASopathy-specific phenotypes needed to calculate VCEP PS4 points.	cspec clinvar
PS5	N/A	PS5 is not a standard ACMG/AMP criterion. It is not included in the RASopathy VCEP framework. No applicable rule exists for this criterion code.	cspec
PM1	Met	The variant p.Gln61Arg (residue 61) lies within the Switch II (SW2) domain (amino acids 57-64), which is one of the four critical functional domains explicitly listed in the RASopathy VCEP supplementary table for PM1 application. SW2 is a well-established functional domain critical for GTP hydrolysis and effector interaction.	cspec vcep_alignment_with_pm1_domains_pptx PMID:20194776
PM2	Met	The variant is absent from gnomAD population databases (v2.1, v4.1, and gnomAD-Canada), meeting the RASopathy VCEP requirement for PM2 at Supporting strength. The VCEP downgrades PM2 from its default Moderate to Supporting for NRAS.	cspec gnomad_v2 gnomad_v4 gnomad_canada
PM3	N/A	PM3 applies to recessive disorders where the variant is detected in trans with a pathogenic variant. RASopathies are autosomal dominant gain-of-function disorders; PM3 is not applicable.	cspec
PM4	N/A	PM4 applies to protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants. This variant is a single-nucleotide missense substitution and does not alter protein length.
PM5	Met	Multiple alternative pathogenic residue changes at NRAS codon 61 have been established as pathogenic. N-RAS Q61K (c.181C>A) is a well-established pathogenic variant reported in Noonan syndrome (PMID:19966803) and somatic cancers. N-RAS Q61L (c.182A>T) is also pathogenic. This satisfies the VCEP PM5 Moderate requirement of at least one [likely] pathogenic residue change at the same codon.	cspec clinvar
PM6	Not met	No assumed de novo observations (without confirmed parentage) were identified in the case materials. The RASopathy VCEP requires point-based scoring in conjunction with PS2; no qualifying data available.	cspec
PP1	Not met	No co-segregation data in affected family members is available. The RASopathy VCEP requires ≥3 informative meioses for Supporting, ≥5 for Moderate, and ≥7 for Strong. No segregation data identified in case materials.	cspec
PP2	N/A	The RASopathy VCEP marks PP2 as Not Applicable because the NRAS missense z-score is <3.09 in gnomAD.	cspec
PP3	Met	The REVEL score for this variant is 0.888, which is ≥0.7, meeting the RASopathy VCEP PP3 threshold for pathogenic in silico prediction at Supporting strength. SpliceAI predicts no significant splice impact (max delta = 0.01), which is consistent with a missense effect rather than splicing.	cspec revel spliceai
PP4	N/A	The RASopathy VCEP marks PP4 as Not Applicable; phenotype specificity is instead addressed through the PS4 point-based scoring system.	cspec
PP5	N/A	The RASopathy VCEP explicitly marks PP5 as Not Applicable, per ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation.	cspec
BA1	Not met	The RASopathy VCEP BA1 threshold is gnomAD filtering allele frequency ≥0.05%. The variant is absent from gnomAD v2.1 and v4.1, with an allele frequency of 0.0%. BA1 is not met.	cspec gnomad_v2 gnomad_v4
BS1	Not met	The RASopathy VCEP BS1 threshold is gnomAD filtering allele frequency ≥0.025%. The variant is absent from gnomAD v2.1 and v4.1. BS1 is not met.	cspec gnomad_v2 gnomad_v4
BS2	Not met	No observation of this variant in healthy adult individuals. The RASopathy VCEP requires point-based scoring based on healthy homozygote or heterozygote individuals; no such data are available.	cspec
BS3	N/A	The RASopathy VCEP marks BS3 as Not Applicable. Functional studies for NRAS in the RASopathy context are addressed through PS3 only; approved assays all show damaging effects consistent with gain-of-function mechanism.	cspec
BS4	Not met	No lack-of-segregation data are available. The RASopathy VCEP requires only one informative meiosis showing lack of segregation; no such data were identified in case materials.	cspec
BP1	N/A	The RASopathy VCEP specifies BP1 for truncating variants (nonsense, frameshift, canonical splice sites, initiation codon, gene deletions) in genes where gain-of-function is the disease mechanism. This variant is a missense substitution, not a truncating variant. BP1 does not apply.	cspec
BP2	Not met	No evidence of an alternative molecular cause of RASopathy in the same gene, and no phenotype data inconsistent with RASopathy explained by a different variant. No BP2 points can be awarded.	cspec
BP3	N/A	BP3 applies to in-frame deletions/insertions in repetitive regions without known function. This variant is a single-nucleotide missense substitution, not an in-frame indel.
BP4	Not met	The RASopathy VCEP BP4 threshold for missense variants is REVEL ≤0.3. The REVEL score for this variant is 0.888, which strongly predicts a deleterious effect. BP4 is not met.	cspec revel
BP5	Not met	No evidence of an alternative molecular cause of RASopathy in a different gene, and no phenotype data inconsistent with RASopathy explained by a different causative variant. No BP5 points can be awarded.	cspec
BP6	N/A	The RASopathy VCEP explicitly marks BP6 as Not Applicable, per ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation.	cspec
BP7	N/A	BP7 applies only to synonymous (silent) variants with no predicted splice impact and low nucleotide conservation. This variant is a missense change (c.182A>G, p.Gln61Arg) and does not qualify for BP7.	cspec

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