The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene label mismatch: HRAS vs undefined
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computed assertion could be determined for this classification!


Variant: NM_005343.4(HRAS):c.173C>T (p.Thr58Ile)

CA341206

12610 (ClinVar)

Gene: HRAS
Condition: RASopathy
Inheritance Mode: Autosomal dominant inheritance
UUID: 4fa14d9d-3bce-4dd8-affa-771b6298c4fc
Approved on: 2024-12-03
Published on: 2025-03-31

HGVS expressions

NM_005343.4:c.173C>T
NM_005343.4(HRAS):c.173C>T (p.Thr58Ile)
NC_000011.10:g.533883G>A
CM000673.2:g.533883G>A
NC_000011.9:g.533883G>A
CM000673.1:g.533883G>A
NC_000011.8:g.523883G>A
NG_007666.1:g.6668C>T
ENST00000397594.7:c.173C>T
ENST00000417302.7:c.173C>T
ENST00000417302.6:c.173C>T
ENST00000462734.2:c.173C>T
ENST00000311189.8:c.173C>T
ENST00000311189.7:c.173C>T
ENST00000397594.5:c.173C>T
ENST00000397596.6:c.173C>T
ENST00000417302.5:c.173C>T
ENST00000451590.5:c.173C>T
ENST00000468682.2:n.661C>T
ENST00000479482.1:n.94C>T
ENST00000493230.5:c.173C>T
NM_001130442.1:c.173C>T
NM_005343.2:c.173C>T
NM_176795.3:c.173C>T
NM_001130442.2:c.173C>T
NM_001318054.1:c.-147C>T
NM_005343.3:c.173C>T
NM_176795.4:c.173C>T
NM_001318054.2:c.-147C>T
NM_001130442.3:c.173C>T
NM_176795.5:c.173C>T
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Pathogenic

Met criteria codes 7
PP2 PP3 PM1 PS1 PS2 PM2_Supporting PS4_Moderate
Not Met criteria codes 4
BA1 BP1 BP4 BS1

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for HRAS Version 2.3.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
RASopathy VCEP
The c.173C>T variant in the HRAS gene is a missense variant predicted to cause substitution of threonine by isoleucine at amino acid 58 (p.Thr58Ile). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.777, which is above the threshold of 0.7, evidence that correlates with impact to HRAS function (PP3). This variant resides within a region (amino acids 57 – 64), of HRAS that is defined as a critical functional domain by the ClinGen RASopathy VCEP (PM1). The p.Thr58Ile variant in HRAS is analogous to the same previously established amino acid change in the KRAS gene and the ClinGen RASopathy Expert Panel has defined that the pathogenicity of analogous variants in the HRAS and KRAS genes are correlated based on the assumption that a known functional residue in one gene is equivalent to other functions within that subgroup (PS1). At least 4 independent occurrences of this variant have been detected in patients with a RASopathy, of which 1 was reported as a de novo occurrence (PS2, PS4_Moderate; CeGaT Center for Human Genetics, ClinVar SCV003916655.13; PMIDs: 22488832, 18247425, 23321623, 26888048). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant RASopathies based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: PS1, PS2, PS4_Moderate, PM1, PM2_Supporting, PP3 (Specification Version 2.3, 12/3/2024)
Met criteria codes
PP2
The variant is in HRAS, which has been defined by the ClinGen RASopathy Expert Panel as a gene with low rate of benign missense with missense variants commonly being pathogenic
PP3
The computational predictor REVEL gives a score of 0.777, which is above the threshold of 0.7, evidence that correlates with impact to HRAS function
PM1
Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of HRAS (PM1; PMID 29493581).
PS1
The p.Thr58Ile variant in HRAS is analogous to the same previously established amino acid change in the KRAS gene and the ClinGen RASopathy Expert Panel has defined that the pathogenicity of analogous variants in the HRAS and KRAS genes are correlated based on the assumption that a known functional residue in one gene is equivalent to other functions within that subgroup
PS2
This variant was reported as a de novo occurrence in a proband with a RASopathy (PMID:26888048)
PM2_Supporting
This variant is absent from gnomAD v2.1.1
PS4_Moderate
At least 4 independent occurrences of this variant have been detected in patients with a RASopathy (CeGaT Center for Human Genetics, ClinVar SCV003916655.13; PMIDs: 22488832, 18247425, 23321623, 26888048)
Not Met criteria codes
BA1
This variant is absent from gnomAD v2.1.1
BP1
The variant is in HRAS, which has been defined by the ClinGen RASopathy Expert Panel as a gene with low rate of benign missense with missense variants commonly being pathogenic
BP4
The computational predictor REVEL gives a score of 0.777, which is above the threshold of 0.7, evidence that correlates with impact to HRAS function
BS1
This variant is absent from gnomAD v2.1.1
Curation History
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