Variant classification summary

NM_005343.4:c.173C>T

HRAS · NP_005334.1:p.(Thr58Ile) · NM_005343.4

GRCh37: chr11:533883 G>A · GRCh38: chr11:533883 G>A

Gene: HRAS Transcript: NM_005343.4

Final call

Likely Pathogenic

PS4 moderate PM1 moderate PM6 supporting PP3 supporting PP5 supporting

Variant details

Gene

HRAS

Transcript

NM_005343.4

Protein

NP_005334.1:p.(Thr58Ile)

gnomAD AF

6.198521280763261e-07 (v4.1)

ClinVar

Pathogenic

OncoKB

Inconclusive

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PS4 (Moderate): the exact variant was observed in at least 4 independent individuals with a RASopathy.

2

PM1 (Moderate): Thr58 lies in the Switch II domain (amino acids 57-64), a VCEP-defined critical functional region.

3

PM6 (Supporting): the variant was reported de novo or presumably de novo in multiple affected individuals.

4

PP3 (Supporting): REVEL 0.777 meets the VCEP's >=0.7 threshold for a damaging missense prediction.

5

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

6

Together these satisfy Rule 14 of the ClinGen RASopathy HRAS VCEP (two Moderate plus at least two Supporting), yielding a final classification of Likely Pathogenic.

Final determination: Rule14 of the ClinGen RASopathy VCEP HRAS Version 2.3 criteria-combination framework (Pathogenic.Moderate ==2 AND Pathogenic.Supporting >=2) is satisfied, yielding Likely 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: this is a missense change, not a null variant (no stop, frameshift, or splice-site loss), and the RASopathy VCEP marks PVS1 as not applicable for HRAS.	cspec pvs1_variant_assessment
PS1	N/A	Not applicable: this variant itself produces p.Thr58Ile, so it cannot serve as its own PS1 comparator; no analogous pathogenic change was identified in a paralog gene.
PS2	Not assessed	Not assessed: parental testing did not confirm both parents were negative, so confirmed de novo status could not be established.	cspec PMID:18247425 PMID:26888048 PMID:22488832
PS3	Not assessed	Not assessed: no VCEP-approved functional assay (e.g., RAS or MEK activation) was performed on this HRAS variant; functional data exist only for the analogous change in KRAS.
PS4	Met	Met (Moderate): the exact variant was observed in at least 4 independent individuals with a RASopathy, meeting the 3-point threshold for PS4 Moderate.	clinvar cspec
PM1	Met	Met (Moderate): Thr58 falls in the Switch II domain (amino acids 57-64), a critical functional region where the VCEP applies PM1 at Moderate strength.	cspec vcep_alignment_with_pm1_domains_pptx
PM2	Not met	Not met: the variant is present in gnomAD v4.1 at 1/1,613,288 alleles, so it does not meet the VCEP's requirement of absence from population databases.	cspec gnomad_v2 gnomad_v4 gnomad_canada
PM3	N/A	Not applicable: HRAS-related RASopathy is autosomal dominant, so the recessive-allele criterion PM3 does not apply.	cspec
PM4	N/A	Not applicable: a single-nucleotide missense substitution does not alter protein length, so the in-frame indel/stop-loss criterion PM4 does not apply.	cspec
PM5	Not assessed	Not assessed: insufficient evidence was available; no other pathogenic amino acid change at codon 58 (e.g., Thr58Ala or Thr58Ser) was identified.	pm5_candidates
PM6	Met	Met (Supporting): the variant arose de novo or presumably de novo in multiple affected individuals, though parental confirmation was not fully documented.	cspec PMID:18247425 PMID:26888048
PP1	Not met	Not met: father-to-son transmission provides one informative meiosis, below the three required for PP1 Supporting.	cspec PMID:22488832
PP2	N/A	Not applicable: the RASopathy VCEP explicitly marks PP2 as not applicable for HRAS.	cspec
PP3	Met	Met (Supporting): the REVEL score of 0.777 exceeds the VCEP's >=0.7 threshold for a damaging missense prediction.	cspec revel
PP4	N/A	Not applicable: the RASopathy VCEP explicitly marks PP4 as not applicable 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: at 0.00006% allele frequency (1/1,613,288 alleles), the variant is far below the 0.05% BA1 threshold.	cspec gnomad_v4
BS1	Not met	Not met: the highest subpopulation frequency is 0.01650% (Middle Eastern), below the 0.025% BS1 threshold.	cspec gnomad_v4
BS2	Not assessed	Not assessed: no evidence showed the variant in a clinically unaffected adult; zero homozygotes in gnomAD does not establish benign carrier status.	cspec gnomad_v4
BS3	N/A	Not applicable: the RASopathy VCEP explicitly designates BS3 as not applicable for HRAS.	cspec
BS4	Not met	Not met: the variant segregates with disease (affected father to affected son), with no affected non-carrier reported to contradict segregation.	cspec PMID:22488832
BP1	N/A	Not applicable: BP1 applies only to truncating variants, and this missense change does not truncate the protein.	cspec
BP2	Not assessed	Not assessed: no second pathogenic HRAS variant or documented cis/trans phase was available, so an alternative same-gene cause could not be evaluated.	cspec clinvar
BP3	N/A	Not applicable: this is a missense substitution, not an in-frame indel in a repetitive region.	cspec
BP4	Not met	Not met: the REVEL score of 0.777 is well above the <=0.3 BP4 threshold for a benign prediction.	cspec revel
BP5	Not assessed	Not assessed: no competing diagnosis or alternative molecular cause was established in individuals carrying this variant.
BP6	N/A	Not applicable: the expert panel classified this variant as Pathogenic, not Benign, so BP6 does not apply.	clinvar cspec
BP7	N/A	Not applicable: BP7 applies only to synonymous or intronic variants, and this is a missense change.	cspec

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