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_004985.4(KRAS):c.173C>T (p.Thr58Ile)

CA256480

12588 (ClinVar)

Gene: KRAS
Condition: Noonan syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: be68e302-48f4-4cb4-80a8-915ac3fff981

HGVS expressions

NM_004985.4:c.173C>T
NM_004985.4(KRAS):c.173C>T (p.Thr58Ile)
NM_033360.3:c.173C>T
ENST00000256078.8:c.173C>T
ENST00000311936.7:c.173C>T
ENST00000557334.5:c.112-17440C>T
NC_000012.12:g.25227351G>A
CM000674.2:g.25227351G>A
NC_000012.11:g.25380285G>A
CM000674.1:g.25380285G>A
NC_000012.10:g.25271552G>A
NG_007524.1:g.28570C>T

Pathogenic

Met criteria codes 6
PM6_Strong PS3 PP3 PP2 PM2 PM1
Not Met criteria codes 1
PS1

Evidence Links 4

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 KRAS has been reported in the literature as an unconfirmed de novo occurrence in a patient with clinical features of a RASopathy (PM6_Strong; PMID 23321623, 20112233, 16921267, 16474405, 22488832, 18247425, 20949621). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). In vitro functional studies provide some evidence that the p.Thr58Ile variant may impact protein function (PS3; PMID: 23321623, 20949621, 16921267). 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 KRAS (PM1; PMID 29493581). The variant is located in the KRAS 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). 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_Strong, PS3, PM2, PM1, PP2, PP3.
Met criteria codes
PM6_Strong
The c.173C>T (p.Thr58Ile) variant in KRAS has been reported in the literature as an unconfirmed de novo occurrence in a patient with clinical features of a RASopathy (PM6; PMID 23321623, 20112233, 16921267, 16474405).
The c.173C>T (p.Thr58Ile) variant in KRAS has been reported in the literature as an unconfirmed de novo occurrence in a patient with clinical features of a RASopathy (PM6; PMID 23321623, 20112233, 16921267, 16474405). PubMed:16921267
The c.173C>T (p.Thr58Ile) variant in KRAS has been reported in the literature as an unconfirmed de novo occurrence in a patient with clinical features of a RASopathy (PM6; PMID 23321623, 20112233, 16921267, 16474405). PubMed:20112233
The c.173C>T (p.Thr58Ile) variant in KRAS has been reported in the literature as an unconfirmed de novo occurrence in a patient with clinical features of a RASopathy (PM6; PMID 23321623, 20112233, 16921267, 16474405). PubMed:23321623
The c.173C>T (p.Thr58Ile) variant in KRAS has been reported in the literature as an unconfirmed de novo occurrence in a patient with clinical features of a RASopathy (PM6; PMID 23321623, 20112233, 16921267, 16474405). PubMed:16474405
PS3
In vitro functional studies provide some evidence that the p.Thr58Ile variant may impact protein function (PS3; PMID: 23321623, 20949621, 16921267).
PP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP2
The variant is located in the KRAS 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
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 KRAS (PM1; PMID 29493581).
Not Met criteria codes
PS1
The p.Thr58Ile variant in KRAS is analogous to the same previously established amino acid change in the HRAS gene and the ClinGen RASopathy Expert Panel has defined that the pathogenicities of analogous variants in the KRAS and HRAS 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).
Approved on: 2017-04-03
Published on: 2018-12-10
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