Variant classification summary

NM_001130442.2:c.34G>A

HRAS · NP_001123914.1:p.(Gly12Ser) · NM_001130442.2

GRCh37: chr11:534289 C>T · GRCh38: chr11:534289 C>T

Gene: HRAS Transcript: NM_001130442.2

Final call

Pathogenic

PS2 strong PS3 supporting PS4 strong PM1 moderate PM2 supporting PP5 supporting

Variant details

Gene

HRAS

Transcript

NM_001130442.2

Protein

NP_001123914.1:p.(Gly12Ser)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PS2 (Strong): de novo origin confirmed by parental genotyping in multiple Costello syndrome families.

2

PS3 (Supporting): functional studies show increased RAS-GTP loading and downstream MEK/ERK activation, consistent with the G12 gain-of-function mechanism.

3

PS4 (Strong): found in 30 of 37 HRAS-positive Costello syndrome patients in an independent 43-case series.

4

PM1 (Moderate): Gly12 lies in the P-loop (residues 10-17), a critical functional domain.

5

PM2 (Supporting): absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0.

6

PP5 (Supporting): the ClinGen RASopathy Variant Curation Expert Panel classified this exact variant as Pathogenic.

7

Overall Pathogenic: PS2 (Strong) plus PS4 (Strong) satisfy the VCEP's Rule1 and Rule5 combination rules.

Final determination: Rule5 of the ClinGen RASopathy VCEP HRAS v2.3 criteria-combination framework (>=2 criteria from the PS1/PS2/PS4/PM5_Strong/PM6_Strong/PP1_Strong strong-tier partition) is satisfied by PS2 (strong) and PS4 (strong), independently corroborated by Rule1 (>=1 of the same list), 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	Not applicable: p.Gly12Ser is a missense change, not a loss-of-function (null) variant.	cspec
PS1	Not assessed	Not assessed: no independently established pathogenic variant producing the same p.Gly12Ser amino acid change was available as a comparator.
PS2	Met	Met (Strong): de novo origin was confirmed by parental genotyping in multiple Costello syndrome families, meeting the VCEP two-point Strong threshold.	cspec PMID:16170316 PMID:17054105
PS3	Met	Met (Supporting): functional studies show increased RAS-GTP loading and downstream MEK/ERK activation in VCEP-approved assay categories. Flagged for human review: primary assay publications not yet independently verified.	clinvar vcep_svi_rasopathy_vcep_v2_approved_functional_studies cspec
PS4	Met	Met (Strong): the variant was found in 30 of 37 HRAS-positive Costello syndrome patients, exceeding the VCEP's five-point Strong threshold.	cspec PMID:16170316 PMID:16443854 PMID:16881968 PMID:17054105
PM1	Met	Met (Moderate): Gly12 lies in the P-loop (residues 10-17), a VCEP-designated critical functional domain.	cspec vcep_alignment_with_pm1_domains_pptx
PM2	Met	Met (Supporting): absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 population databases.	cspec gnomad_v2 gnomad_v4 gnomad_canada
PM3	N/A	Not applicable: HRAS Costello syndrome is autosomal dominant, so a criterion requiring a pathogenic variant in trans does not apply.	cspec
PM4	N/A	Not applicable: a single amino acid substitution with no change in protein length.	cspec
PM5	Not assessed	Not assessed: insufficient evidence was available on other pathogenic codon-12 residue changes (e.g., p.Gly12Ala, p.Gly12Cys) needed as comparators.	pm5_candidates
PM6	Not met	Not met: de novo origin is already confirmed with parental genotyping and paternity verification, so it is scored under PS2 rather than assumed.	cspec PMID:16170316 PMID:17054105
PP1	Not assessed	Not assessed: no affected-relative segregation data with informative meioses was available.	cspec PMID:16170316 PMID:17054105
PP2	N/A	Not applicable: the RASopathy VCEP specification excludes this criterion for HRAS.	cspec
PP3	Not met	Not met: REVEL score 0.695 falls below the VCEP's 0.7 threshold, and SpliceAI (max delta 0.00) shows no splice impact.	cspec revel spliceai
PP4	N/A	Not applicable: the RASopathy VCEP specification excludes this criterion for HRAS.	cspec
PP5	Met	Met (Supporting): the ClinGen RASopathy Variant Curation Expert Panel classified this exact variant as Pathogenic.	clinvar
BA1	Not met	Not met: absent from gnomAD, far below the required 0.05% allele frequency threshold.	cspec gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	Not met: absent from gnomAD, below the required 0.025% allele frequency threshold.	cspec gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	Not assessed: no documented healthy adult carrying the variant was identified.	cspec gnomad_v2 gnomad_v4 gnomad_canada
BS3	N/A	Not applicable: the RASopathy VCEP specification excludes this criterion for HRAS.	cspec
BS4	Not assessed	Not assessed: no informative relatives showing the variant failing to segregate with disease were documented.	cspec PMID:16170316 PMID:17054105
BP1	N/A	Not applicable: BP1 applies only to truncating variants, and p.Gly12Ser is a missense change.	cspec
BP2	Not assessed	Not assessed: no evidence established the variant's phase (in cis or trans) relative to another pathogenic variant.	cspec
BP3	N/A	Not applicable: BP3 applies to in-frame indels in repetitive regions, not to missense substitutions.	cspec
BP4	Not met	Not met: REVEL score 0.695 is well above the VCEP's 0.3 threshold for benign impact.	cspec revel
BP5	Not assessed	Not assessed: no alternate molecular diagnosis was documented for the affected individuals.	cspec PMID:16170316 PMID:16443854 PMID:16881968 PMID:17054105
BP6	Not met	Not met: the ClinVar expert-panel classification for this exact variant is Pathogenic, not Benign.	clinvar
BP7	N/A	Not applicable: BP7 applies to synonymous or non-coding variants, not missense changes.	cspec

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.