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

CA256478

12587 (ClinVar)

Gene: KRAS
Condition: Noonan syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 583866a1-1915-4ccd-bc75-8672ca18c8e4
Approved on: 2018-11-15
Published on: 2018-12-10

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 PM6_Strong PM5 PM2
Not Met criteria codes 1
PS2

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
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
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).
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
Not Met criteria codes
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
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