Evidence Repository
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 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_005343.3(HRAS):c.175G>A (p.Ala59Thr)

CA176353

40435 (ClinVar)

Gene: HRAS
Condition: RASopathy
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 2bb21939-344a-41a8-be46-3787926538b9
Approved on: 2024-09-17
Published on: 2024-10-02

HGVS expressions

NM_005343.3:c.175G>A
NM_005343.3(HRAS):c.175G>A (p.Ala59Thr)
NC_000011.10:g.533881C>T
CM000673.2:g.533881C>T
NC_000011.9:g.533881C>T
CM000673.1:g.533881C>T
NC_000011.8:g.523881C>T
NG_007666.1:g.6670G>A
ENST00000397594.7:c.175G>A
ENST00000417302.7:c.175G>A
ENST00000417302.6:c.175G>A
ENST00000462734.2:c.175G>A
ENST00000311189.8:c.175G>A
ENST00000311189.7:c.175G>A
ENST00000397594.5:c.175G>A
ENST00000397596.6:c.175G>A
ENST00000417302.5:c.175G>A
ENST00000451590.5:c.175G>A
ENST00000468682.2:n.663G>A
ENST00000479482.1:n.96G>A
ENST00000493230.5:c.175G>A
NM_001130442.1:c.175G>A
NM_005343.2:c.175G>A
NM_176795.3:c.175G>A
NM_001130442.2:c.175G>A
NM_001318054.1:c.-145G>A
NM_176795.4:c.175G>A
NM_005343.4:c.175G>A
NM_001318054.2:c.-145G>A
NM_001130442.3:c.175G>A
NM_176795.5:c.175G>A
More

Likely Pathogenic

Met criteria codes 5
PS4_Moderate PP3 PP1 PM1 PM2_Supporting
Not Met criteria codes 4
BP4 BA1 PP2 BS1

Evidence Links 1

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for HRAS Version 2.1.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
RASopathy VCEP
The c.175G>A variant in the HRAS gene is a missense variant predicted to cause substitution of alanine by threonine at amino acid 59 (p.Ala59Thr). This variant was absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.755 supporting deleterious 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 c.175G>A (p.Ala59Thr) variant has been identified in at least 3 independent occurrences in patients with a RASopathy (PS4_Moderate; GeneDx, Partners Laboratory for Molecular Medicine, Invitae internal data, ClinVar SCV000198374.4, SCV000950586.1). Moreover, this variant has been reported to segregate with clinical features of a RASopathy in at least 3 family members (PP1; Partners Laboratory for Molecular Medicine internal data, ClinVar SCV000198374.4). In summary, this variant meets criteria to be classified as likely pathogenic for autosomal dominant RASopathies based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: PS4_Moderate, PM1, PM2_Supporting, PP1, PP3 (Specification Version 2.1, 09/17/2024)
Met criteria codes
PS4_Moderate
The c.175G>A (p.Ala59Thr) variant has been identified in at least 3 independent occurrences in patients with Costello syndrome (PS4_Moderate; GeneDx, Partners Laboratory for Molecular Medicine, Invitae internal data, ClinVar SCV000950586.1, SCV000198374.4).
PP3
The computational predictor REVEL gives a score of 0.755 supporting deleterious impact to HRAS function (PP3).
PP1
The p.Ala59Thr variant in HRAS has been reported to segregate with clinical features of a RASopathy in at least 3 family members (PP1; Partners Laboratory for Molecular Medicine internal data, ClinVar SCV000198374.4).
PM1
The variant is in a location (amino acids 57 – 64), that has been defined by the ClinGen RASopathy Expert Panel to be a critical functional domain of HRAS (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). PubMed:29493581
PM2_Supporting
This variant was absent from gnomAD v4.1.0.
Not Met criteria codes
BP4
The computational predictor REVEL gives a score of 0.755 supporting deleterious impact to HRAS function (PP3).
BA1
This variant was absent from gnomAD v4.1.0.
PP2
Not applicable for HRAS
BS1
This variant was absent from gnomAD v4.1.0.
Curation History
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