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]

Link to SEPIO compliant JSON-LD document

Variant: NM_005343.3(HRAS):c.350A>G (p.Lys117Arg)

CA256490

12605 (ClinVar)

Gene: LRRC56

Condition: Costello syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 42e841f0-7121-4d9d-a2ae-ebc27adacd88

HGVS expressions

NM_005343.3:c.350A>G

NM_005343.3(HRAS):c.350A>G (p.Lys117Arg)

NM_001130442.1:c.350A>G

NM_005343.2:c.350A>G

NM_176795.3:c.350A>G

NM_001130442.2:c.350A>G

NM_001318054.1:c.31A>G

NM_176795.4:c.350A>G

NM_005343.4:c.350A>G

ENST00000311189.7:c.350A>G

ENST00000397594.5:c.350A>G

ENST00000397596.6:c.350A>G

ENST00000417302.5:c.350A>G

ENST00000451590.5:c.350A>G

ENST00000462734.1:n.43A>G

ENST00000478324.5:n.60A>G

ENST00000479482.1:n.271A>G

ENST00000493230.5:c.350A>G

NC_000011.10:g.533553T>C

CM000673.2:g.533553T>C

NC_000011.9:g.533553T>C

CM000673.1:g.533553T>C

NC_000011.8:g.523553T>C

NG_007666.1:g.6998A>G

Pathogenic

PM6_Strong PS3 PP3 PM1 PM2

Evidence Links 3

Expert Panel

RASopathy VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

RASopathy VCEP

The c.350A>G (p.Lys117Arg) variant in HRAS has been reported in the literature in at least 2 unconfirmed de novo occurrences in patients with clinical features of a RASopathy (PM6_Strong; PMID 16443854, 16155195). In vitro functional studies provide some evidence that the p.Lys117Arg variant may impact protein function (PS3; PMID 17979197, 21850009). 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). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). Computational prediction tools and conservation analysis suggest that the p.Lys117Arg variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. ACMG/AMP criteria applied: PM6_Strong, PS3, PM1, PM2, PP3.

PM6_Strong

PS3

In vitro functional studies provide some evidence that the p.Lys117Arg variant may impact protein function (PS3; PMID 17979197, 21850009).

In vitro functional studies provide some evidence that the p.Lys117Arg variant may impact protein function (PS3; PMID 17979197, 21850009). PubMed:21850009

PP3

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

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).

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

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

Approved on: 2017-04-03

Published on: 2018-12-10

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