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Please note this is a beta version of the ClinGen Evidence Repository. This resource is intended to provide access to variant level evidence used and applied by ClinGen Variant Curation Expert Panels in the classification of variants. In this beta version, the evidence is limited to curation notes and referenced literature (PMIDs).

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Criteria Specification: CSpec Registry PDF

Variant: NM_004985.4(KRAS):c.458A>T (p.Asp153Val)

CA256478

12587 (ClinVar)

Gene: KRAS
Condition: Noonan syndrome
Inheritance Mode: Autosomal dominant inheritance

HGVS expressions

NM_004985.4:c.458A>T
NM_004985.4(KRAS):c.458A>T (p.Asp153Val)
NM_033360.3:c.*12A>T
ENST00000256078.8:c.*12A>T
ENST00000311936.7:c.458A>T
ENST00000557334.5:c.119A>T
NC_000012.12:g.25209904T>A
CM000674.2:g.25209904T>A
NC_000012.11:g.25362838T>A
CM000674.1:g.25362838T>A
NC_000012.10:g.25254105T>A
NG_007524.1:g.46017A>T

Pathogenic

Met criteria codes 6
PS3 PP3 PP2 PM5 PM2 PM6_Strong
Unmet criteria codes 1
PS2

Expert Panel

Evidence Links 0

Evidence submitted by expert panel
RASopathy VCEP
The c.458A>T (p.Asp153Val) variant in KRAS 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 16474405, 16474404, 21062266, 21871821, 24703799, 16773572). In vitro functional studies provide some evidence that the p.Asp153Val variant may impact protein function (PS3; PMID 20949621). The p.Asp153Val variant in KRAS has been reported in the literature in at least 4 patients with clinical features of a RASopathy (PS4_Moderate; LMM internal data GTR Lab ID: 21766, ClinVar SCV000203924.4; PMID 16474405, 16474404, 21062266, 21871821, 24703799, 16773572). 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, PS4_Moderate.
Met criteria codes
PS3
In vitro functional studies provide some evidence that the p.Asp153Val variant may impact protein function (PS3; PMID 20949621).
PP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM5
A different pathogenic missense variant has been previously identified at this codon of KRAS which may indicate that this residue is critical to the function of the protein (PM5; ClinVar 12590).
PM2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM6_Strong
The c.458A>T (p.Asp153Val) variant in KRAS 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 16474405, 16474404, 21062266, 21871821, 24703799, 16773572).
Unmet criteria codes
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Approved on: 2018-11-15
Published on: 2018-12-10
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