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_176795.4(HRAS):c.173C>T (p.Thr58Ile)

CA341206

12610 (ClinVar)

Gene: LRRC56
Condition: Costello syndrome
Inheritance Mode: Autosomal dominant inheritance
UUID: 4fa14d9d-3bce-4dd8-affa-771b6298c4fc

HGVS expressions

NM_176795.4:c.173C>T
NM_176795.4(HRAS):c.173C>T (p.Thr58Ile)
NM_001130442.1:c.173C>T
NM_005343.2:c.173C>T
NM_176795.3:c.173C>T
NM_001130442.2:c.173C>T
NM_001318054.1:c.-147C>T
NM_005343.3:c.173C>T
NM_005343.4:c.173C>T
ENST00000311189.7:c.173C>T
ENST00000397594.5:c.173C>T
ENST00000397596.6:c.173C>T
ENST00000417302.5:c.173C>T
ENST00000451590.5:c.173C>T
ENST00000468682.2:n.661C>T
ENST00000479482.1:n.94C>T
ENST00000493230.5:c.173C>T
NC_000011.10:g.533883G>A
CM000673.2:g.533883G>A
NC_000011.9:g.533883G>A
CM000673.1:g.533883G>A
NC_000011.8:g.523883G>A
NG_007666.1:g.6668C>T

Pathogenic

Met criteria codes 7
PS4_Supporting PS1 PM6 PM2 PM1 PP3 PP2

Evidence Links 7

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
RASopathy VCEP
The c.173C>T (p.Thr58Ile) variant in HRAS has been reported in the literature as an unconfirmed de novo occurrence in a patient with clinical features of a RASopathy (PM6; PMID 20112233, 16474405). Also, at least 2 independent occurrences of this variant have been detected in patients with a RASopathy (PS4_Supporting; PMID: 22488832, 18247425, 23321623, 20949621, 16921267). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The p.Thr58Ile variant in HRAS is analogous to the same previously established amino acid change in the KRAS gene and the ClinGen RASopathy Expert Panel has defined that the pathogenicities of analogous variants in the HRAS and KRAS genes are correlated based on the assumption that a known functional residue in one gene is equivalent to other functions within that subgroup (PS1; 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). The variant is in HRAS, which has been defined by the ClinGen RASopathy Expert Panel as a gene with low rate of benign missense with missense variants commonly being pathogenic (PP2; PMID 29493581). Computational prediction tools and conservation analysis suggest that the p.Thr58Ile variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PM6, PS4_Supporting, PM2, PS1, PM1, PP2, PP3.
Met criteria codes
PS4_Supporting
Also, at least 2 independent occurrences of this variant have been detected in patients with a RASopathy (PS4_Supporting; PMID: 22488832, 18247425, 23321623, 20949621, 16921267).

PS1
The p.Thr58Ile variant in HRAS is analogous to the same previously established amino acid change in the KRAS gene and the ClinGen RASopathy Expert Panel has defined that the pathogenicities of analogous variants in the HRAS and KRAS genes are correlated based on the assumption that a known functional residue in one gene is equivalent to other functions within that subgroup (PS1; 29493581).
PM6
The p.Thr58Ile variant in HRAS has been reported in the literature as an unconfirmed de novo occurrence in a patient with clinical features of a RASopathy (PM6; PMID 20112233, 16474405).

PM2
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).
PP3
Computational prediction tools and conservation analysis suggest that the p.Thr58Ile variant may impact the protein (PP3).
PP2
The variant is in HRAS, which has been defined by the ClinGen RASopathy Expert Panel as a gene with low rate of benign missense with missense variants commonly being pathogenic (PP2; PMID 29493581).
Approved on: 2017-04-03
Published on: 2018-12-10
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