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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Variant: NM_005343.3(HRAS):c.175G>A (p.Ala59Thr)

CA176353

40435 (ClinVar)

Gene: HRAS

Condition: Costello syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 2bb21939-344a-41a8-be46-3787926538b9

HGVS expressions

NM_005343.3:c.175G>A

NM_005343.3(HRAS):c.175G>A (p.Ala59Thr)

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

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

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

Likely Pathogenic

PP1 PP3 PP2 PM2 PM1 PS4_Moderate

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>A (p.Ala59Thr) variant in HRAS has been identified in at least 3 independent occurrences in patients with a RASopathy (PS4_Moderate; GeneDx, Partners LMM, Invitae internal data; ClinVar SCV000198374, SCV000950586). The p.Ala59Thr variant segregated with clinical features of a RASopathy in at least 3 family members (PP1; GeneDx, Partners LMM internal data). This variant was absent from large population studies (PM2; gnomad.broadinstitute.org). 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). Computational prediction tools and conservation analysis suggest that the p.Ala59Thr variant may impact the protein (PP3). 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): PM1, PM2, PS4_Moderate, PP1, PP2, 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).

PP3

Computational prediction tools and conservation analysis suggest that the p.Ala59Thr variant may impact the protein (PP3).

PP2

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)

PM2

Absent from both versions of gnomAD.

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

PS4_Moderate

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 SCV000950586.1, SCV000198374.4).

Approved on: 2021-01-25

Published on: 2021-01-25

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