Variant classification summary

NM_005343.4:c.35G>T

HRAS · NP_005334.1:p.(Gly12Val) · NM_005343.4

GRCh37: chr11:534288 C>A · GRCh38: chr11:534288 C>A

Gene: HRAS Transcript: NM_005343.4

Final call

Pathogenic

PS1 strong PS2 moderate PS3 moderate PM1 moderate PM2 supporting PM6 moderate PP3 supporting

Variant details

Gene

HRAS

Transcript

NM_005343.4

Protein

NP_005334.1:p.(Gly12Val)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Pathogenic: the exact p.Gly12Val change is established as Pathogenic in ClinVar, satisfying PS1 at strong strength.

2

Pathogenic: one verified de novo Costello syndrome proband supports PS2 at moderate strength.

3

Pathogenic: p.Gly12Val is a P/LP control in three approved HRAS pathway assays, supporting PS3 at moderate strength.

4

Pathogenic: residue 12 lies within the approved HRAS P-loop domain, satisfying PM1 at moderate strength.

5

Pathogenic: the variant is absent from gnomAD v2.1, v4.1, and non-cancer subsets, satisfying PM2 at supporting strength.

6

Pathogenic: a clinical submission describes the exact variant as likely de novo, supporting PM6 at moderate strength.

7

Pathogenic: REVEL 0.789 exceeds the HRAS VCEP PP3 threshold of 0.7, satisfying PP3 at supporting strength.

Final determination: HRAS VCEP Rule6 is satisfied by one strong pathogenic criterion (PS1) and at least three moderate pathogenic criteria (PS2, PM1, and PM6), yielding 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: the HRAS VCEP explicitly marks PVS1 as not applicable, and this variant is a missense p.(Gly12Val) substitution.	cspec pvs1_variant_assessment
PS1	Met	Met at strong: ClinVar records the exact p.Gly12Val change as Pathogenic, satisfying the VCEP's same-amino-acid-change rule.	cspec clinvar
PS2	Met	Met, Moderate: one Costello syndrome proband had the exact p.Gly12Val variant verified de novo, supporting the VCEP's 2-point PS2 tier.	cspec clinvar
PS3	Met	Met at Moderate: G12V is a P/LP validation control in three approved HRAS assay types, exceeding the VCEP requirement of two different approved assays.	cspec vcep_svi_rasopathy_vcep_v2_approved_functional_studies
PS4	Not assessed	Not assessed: no verified PS4 point total, case-control counts, or phenotype-specific proband evidence is available to compare with the VCEP thresholds of ≥1, ≥3, or ≥5 points.	cspec
PM1	Met	Met at moderate: residue 12 lies within the VCEP-approved HRAS P-loop domain spanning amino acids 10-17.	cspec vcep_alignment_with_pm1_domains_pptx
PM2	Met	Met at Supporting: the variant is absent from gnomAD v2.1, v4.1, and non-cancer subsets, satisfying the VCEP's PM2 absence-from-controls rule.	cspec gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: the HRAS VCEP specification explicitly marks PM3 as Not Applicable.	cspec
PM4	N/A	Not applicable: PM4 concerns protein-length changes, whereas NM_005343.4:c.35G>T is a missense p.(Gly12Val) substitution with no length change.	cspec pvs1_variant_assessment
PM5	Not assessed	Not assessed: the available comparator search found 0 same-residue candidates, so the VCEP's one-comparator Moderate threshold cannot be confirmed.	cspec pm5_candidates
PM6	Met	Met, Moderate: the exact variant was considered likely de novo in one proband, with parental germline mosaicism not excluded, supporting 1 VCEP PM6 point.	cspec clinvar
PP1	Not assessed	Not assessed: no affected-relative segregation data or informative-meiosis count is available for the exact variant.
PP2	N/A	Not applicable: the HRAS VCEP excludes PP2 because HRAS has a missense z score below 3.09 in gnomAD.	cspec
PP3	Met	Met at supporting: REVEL score 0.789 exceeds the HRAS VCEP PP3 missense threshold of ≥0.7.	cspec revel
PP4	N/A	Not applicable: the HRAS VCEP explicitly excludes PP4 and directs phenotype evidence to PS4.	cspec
PP5	N/A	Not applicable: the HRAS VCEP states that PP5 is not for use for this VCEP.	cspec
BA1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, so its filtering allele frequency is 0%, below the VCEP's 0.05% BA1 threshold.	cspec gnomad_v2 gnomad_v4
BS1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, so its filtering allele frequency is 0%, below the VCEP's 0.025% BS1 threshold.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: no healthy homozygote or heterozygote observation or VCEP phenotype-specific point assignment is available for this variant.	cspec
BS3	N/A	Not applicable: the HRAS VCEP marks BS3 Not applicable and the approved HRAS assay rows assign BS3_NA, with G12V used as a P/LP control.	cspec vcep_svi_rasopathy_vcep_v2_approved_functional_studies
BS4	Not assessed	Not assessed: no informative non-segregation event is documented to satisfy the one-meiosis BS4 requirement.
BP1	N/A	Not applicable: BP1 is limited to truncating loss-of-function variants, whereas c.35G>T produces the missense change p.Gly12Val.	cspec pvs1_variant_assessment
BP2	Not assessed	Not assessed: no documented phase or qualifying allelic observation establishes the VCEP's minimum BP2 threshold of ≥ (-1) point.	cspec
BP3	N/A	Not applicable: the HRAS VCEP explicitly marks BP3 as not applicable, and this variant is a missense p.(Gly12Val) substitution.	cspec pvs1_variant_assessment
BP4	Not met	Not met: REVEL score 0.789 is above the HRAS VCEP BP4 missense cutoff of ≤0.3.	cspec revel
BP5	Not assessed	Not assessed: no alternative causative variant or VCEP BP5 point total is documented for the required alternative-molecular-cause phenotype assessment.	cspec
BP6	N/A	Not applicable: the HRAS VCEP states that BP6 is not for use for this VCEP.	cspec
BP7	N/A	Not applicable: c.35G>T is a missense coding variant, outside the VCEP BP7 scope for synonymous, intronic, and non-coding variants.	cspec

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