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]
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  • See Evidence submitted by expert panel for details.

Variant: NM_005343.4(HRAS):c.175_176delinsCT (p.Ala59Leu)

CA273607

179260 (ClinVar)

Gene: HRAS
Condition: RASopathy
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 96293b0b-7e4a-4ba8-b473-a9d3c5f4e8fe

HGVS expressions

NM_005343.4:c.175_176delinsCT
NM_005343.4(HRAS):c.175_176delinsCT (p.Ala59Leu)
NM_001130442.1:c.175_176delinsCT
NM_005343.2:c.175_176delinsCT
NM_176795.3:c.175_176delinsCT
NM_001130442.2:c.175_176delinsCT
NM_001318054.1:c.-145_-144delinsCT
NM_005343.3:c.175_176delinsCT
NM_176795.4:c.175_176delinsCT
NM_001318054.2:c.-145_-144delinsCT
NM_001130442.3:c.175_176delinsCT
NM_176795.5:c.175_176delinsCT
ENST00000311189.7:c.175_176delinsCT
ENST00000397594.5:c.175_176delinsCT
ENST00000397596.6:c.175_176delinsCT
ENST00000417302.5:c.175_176delinsCT
ENST00000451590.5:c.175_176delinsCT
ENST00000468682.2:n.663_664delinsCT
ENST00000479482.1:n.96_97delinsCT
ENST00000493230.5:c.175_176delinsCT
NC_000011.10:g.533880_533881delinsAG
CM000673.2:g.533880_533881delinsAG
NC_000011.9:g.533880_533881delinsAG
CM000673.1:g.533880_533881delinsAG
NC_000011.8:g.523880_523881delinsAG
NG_007666.1:g.6670_6671delinsCT

Likely Pathogenic

Met criteria codes 5
PP2 PS4_Supporting PM2 PM6 PM1

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
RASopathy VCEP
The c.175_176delinsCT (p.Ala59Leu) in HRAS was absent from gnomAD (PM2; PMID: 29493581). It has been identified as a de novo occurrence (parentage unconfirmed) in 1 individual with clinical features of a RASopathy (PM6, PS4_Supporting; SCV000205760.4, PMID: 26918529). Furthermore, the p.Ala59Leu variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot of HRAS (PM1; PMID 29493581). The variant is located in the HRAS gene, 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). In summary, this variant meets criteria to be classified as likely pathogenic for RASopathies in an autosomal dominant manner. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PP2, PM1, PM2, PM6, PS4_Supporting.
Met criteria codes
PP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4_Supporting
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM1
PM1 defined hotspots in HRAS: G12, G13, V14, T58, A59, G60, Q61, E62, E63
Approved on: 2021-01-11
Published on: 2021-01-11
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