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

  • See Evidence submitted by expert panel for details.

Variant: NM_005343.4(HRAS):c.367C>T (p.Arg123Cys)

CA296066

180851 (ClinVar)

Gene: HRAS
Condition: RASopathy
Inheritance Mode: Autosomal dominant inheritance
UUID: ddb4f82c-1f78-4470-b901-2ae38923ace4
Approved on: 2020-07-23
Published on: 2020-07-27

HGVS expressions

NM_005343.4:c.367C>T
NM_005343.4(HRAS):c.367C>T (p.Arg123Cys)
NM_001130442.1:c.367C>T
NM_005343.2:c.367C>T
NM_176795.3:c.367C>T
NM_001130442.2:c.367C>T
NM_001318054.1:c.48C>T
NM_005343.3:c.367C>T
NM_176795.4:c.367C>T
NM_001318054.2:c.48C>T
ENST00000311189.7:c.367C>T
ENST00000397594.5:c.367C>T
ENST00000397596.6:c.367C>T
ENST00000417302.5:c.367C>T
ENST00000451590.5:c.367C>T
ENST00000462734.1:n.60C>T
ENST00000478324.5:n.77C>T
ENST00000479482.1:n.288C>T
ENST00000493230.5:c.367C>T
NC_000011.10:g.533536G>A
CM000673.2:g.533536G>A
NC_000011.9:g.533536G>A
CM000673.1:g.533536G>A
NC_000011.8:g.523536G>A
NG_007666.1:g.7015C>T
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Uncertain Significance

Met criteria codes 2
PP2 PP3
Not Met criteria codes 4
BS2 PM2 PM5 PM1

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
RASopathy VCEP
The c.367C>T (p.Arg123Cys) variant in HRAS was present in 0.008674% (3/34586) of Latino alleles in gnomAD (BS1 not met; gnomad.broadinstitute.org). It has been observed in the unaffected parents of probands whose phenotypes were not consistent with RASopathies; however, this evidence does not meet current scoring criteria for BS2 (BS2 not met; GeneDx internal data, ClinVar SCV000207857.9; Baylor Genetics internal data). HRAS 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). Computational prediction tools and conservation analysis suggest that the p.Arg123Cys variant may impact the protein (PP3). In summary, the clinical significance of this variant is uncertain. RASopathy-specific ACMG/AMP criteria applied (PMID: 29493581): PP2, PP3.
Met criteria codes
PP2
The RASopathy EP has defined HRAS to be a missense-constrained gene where pathogenic missense variants are common (PMID: 29493581).
PP3
REVEL 0.769. Not predicted to impact splicing. Conserved in the UCSC database except for Gln in one mammal.
Not Met criteria codes
BS2
Observed in the unaffected parents of probands whose phenotypes were not consistent with RASopathies; however, this evidence does not meet current scoring criteria for BS2 (BS2 not met; GeneDx internal data, ClinVar SCV000207857.9; Baylor Genetics internal data).
PM2
Present in 0.008674% (3/34586) of Latino alleles and 0.002640% (3/113656) of non-Finnish European alleles in gnomAD v2. In v3, present in 0.001549% (1/64570) of non-Finnish European alleles.
PM5
The only other variant in this codon, R123P, is listed as VUS in ClinVar by 1 submitter only.
PM1
Does not occur at aa G12, G13, V14, T58, A59, G60, Q61, E62, or E63.
Curation History
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