Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

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CA378924686

Gene: HRAS

Condition: RASopathy

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 1c7d10c9-878e-4c3c-91bb-eec51553f116

HGVS expressions

NM_001318054.2:c.-145G>T

NC_000011.10:g.533881C>A

CM000673.2:g.533881C>A

NC_000011.9:g.533881C>A

CM000673.1:g.533881C>A

NC_000011.8:g.523881C>A

NG_007666.1:g.6670G>T

NM_001130442.1:c.175G>T

NM_005343.2:c.175G>T

NM_176795.3:c.175G>T

NM_001130442.2:c.175G>T

NM_001318054.1:c.-145G>T

NM_005343.3:c.175G>T

NM_176795.4:c.175G>T

NM_005343.4:c.175G>T

NM_001130442.3:c.175G>T

NM_176795.5:c.175G>T

ENST00000311189.7:c.175G>T

ENST00000397594.5:c.175G>T

ENST00000397596.6:c.175G>T

ENST00000417302.5:c.175G>T

ENST00000451590.5:c.175G>T

ENST00000468682.2:n.663G>T

ENST00000479482.1:n.96G>T

ENST00000493230.5:c.175G>T

Uncertain Significance

PM1 PM2 PP2

PS4 PM5 BS2 PP3

Evidence Links 1

Expert Panel

RASopathy VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

RASopathy VCEP

The c.175G>T (p.Ala59Ser) variant in HRAS was absent from large population studies (PM2; gnomad.broadinstitute.org). It was identified in 1 fetus with clinical features of a RASopathy; however, it was also observed in the proband’s unaffected mother (PS4 not met; Hospital for Sick Children internal data). The variant is located in HRAS, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). 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). Of note, 3 different likely pathogenic missense variants have been previously reported at this codon of HRAS (p.Ala59Thr, ClinVar ID: 40435; p.Ala59Leu, and p.Ala59Phe), which may indicate that this residue is critical to the function of the protein; however, these variants have not yet met criteria to be classified as pathogenic (PM5 not met). In summary, the clinical significance of the p.Ala59Ser variant is uncertain. RASopathy-specific ACMG/AMP criteria applied (PMID: 29493581): PM1, PM2, PP2.

PM1

The ClinGen RASopathy EP has designated the Ala59 residue in HRAS as a mutational hot-spot supporting pathogenicity (PMID: 29493581).

The ClinGen RASopathy EP has designated the Ala59 residue in HRAS as a mutational hot-spot supporting pathogenicity. PubMed:29493581

PM2

Absent from both versions of gnomAD.

PP2

The ClinGen RASopathy EP has defined HRAS as a missense-constrained gene (PMID: 29493581)

PS4

Detected in 1 fetus with increased nuchal translucency, hydrops and echogenic kidneys. However, it was also detected in the unaffected mother (Hospital for Sick Children personal communication).

PM5

The ClinGen RASopathy EP has classified the p.Ala59Thr variant (ClinVar ID: 40435) as likely pathogenic.

BS2

Detected in 1 unaffected parent (Hospital for Sick Children personal communication).

PP3

REVEL 0.694. May impact a 3' cryptic splice site. Entirely conserved in UCSC database.

Approved on: 2021-01-25

Published on: 2021-01-25

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