Gene/Disease Pair: | KRAS : Costello syndrome |
HGNC:6407 | MONDO_0009026 | |
Mode of Inheritance: | Autosomal dominant inheritance (HP:0000006) |
Expert Panel: | RASopathy EP |
SOP: | Gene Clinical Validity Standard Operating Procedures (SOP), Version 5 |
Genetic Evidence
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Case-Level Data
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Evidence Type | Case Information Type | Guidelines | Points | PMIDs/Notes | ||||||
Default | Range | Max | Total | Counted | ||||||||
Variant Evidence
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Autosomal Dominant or X-linked Disorder | Variant is de novo | 2 | 0-3 | 12 |
0
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0 |
Zenker M et al. 2007 Feb (PMID:17056636); Carta C et al. 2006 Jul (PMID:16773572);
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Proband with predicted or proven null variant | 1.5 | 0-2 | 10 | |||||||||
Proband with other variant type with some evidence of gene impact | 0.5 | 0-1.5 | 7 |
0
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0 |
Bertola DR et al. 2007 Apr 28 (PMID:17468812);
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Autosomal Recessive Disease | Two variants in trans and at least one de novo or a predicted/proven null variant | 2 | 0-3 | 12 |
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Two variants (not predicted/proven null) with some evidence of gene impact in trans | 1 | 0-1.5 | ||||||||||
Segregation Evidence | Evidence of segregation in one or more families | Sequencing Method | 0-3 | 3 |
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Total LOD Score | Canditate Gene Sequencing | Exome/Genome or all genes sequenced in linkage region | ||||||||||
2-2.99 | 0.5 | 1 | ||||||||||
3-4.99 | 1 | 2 | ||||||||||
≥5 | 1.5 | 3 | ||||||||||
Case-Control Data
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Case-Control Study Type | Case-Control Quality Criteria | Guidelines | Points | PMIDs/Notes | |||||||
Points/Study | Max | Total | Counted | |||||||||
Single Variant Analysis | 1. Variant Detection Methodology 2. Power 3. Bias and confounding 4. Statistical Significance |
0-6 | 12 |
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Aggregate Variant Analysis | 0-6 |
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Total Genetic Evidence Points (Maximum 12) | 0 |
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Experimental Evidence
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Evidence Category | Evidence Type | Guidelines | Points | PMIDs/Notes | |||||||
Default | Range | Max | Total | Counted | ||||||||
Function | Biochemical Function | 0.5 | 0 - 2 | 2 |
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=PrintWrapperPmid($inputThisData["ExperimentalEvidence"]["Function"]["BiochemicalFunction"], "scoreJson[ExperimentalEvidence][Function][BiochemicalFunction]") ?> | ||||||
Protein Interaction | 0.5 | 0 - 2 | ||||||||||
Expression | 0.5 | 0 - 2 | ||||||||||
Functional Alteration | Patient cells | 1 | 0 - 2 | 2 |
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Non-patient cells | 0.5 | 0 - 1 | ||||||||||
Models | Non-human model organism | 2 | 0 - 4 | 4 | ||||||||
Cell culture model | 1 | 0 - 2 | ||||||||||
Rescue | Rescue in human | 2 | 0 - 4 |
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Rescue in non-human model organism | 2 | 0 - 4 | ||||||||||
Rescue in cell culture model | 1 | 0 - 2 | ||||||||||
Rescue in patient cells | 1 | 0 - 2 | ||||||||||
Total Experimental Evidence Points (Maximum 6) | 0 |
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Assertion criteria | Genetic Evidence (0-12 points) | Experimental Evidence
(0-6 points) |
Total Points
(0-18) |
Replication Over Time (Y/N) | ||
Description | Case-level, family segregation, or case-control data that support the gene-disease association | Gene-level experimental evidence that support the gene-disease association | Sum of Genetic & Experimental
Evidence |
> 2 pubs w/ convincing evidence over time (>3 yrs) | ||
Assigned Points | =$inputThisData["summary"]["GeneticEvidenceTotal"]?> 0 | =$inputThisData["summary"]["ExperimentalEvidenceTotal"]?> 0 | =$inputThisData["summary"]["EvidencePointsTotal"]?> 0 | NO | ||
CALCULATED CLASSIFICATION | LIMITED | 1-6 | ||||
MODERATE | 7-11 | |||||
STRONG | 12-18 | |||||
DEFINITIVE | 12-18 AND replication over time | |||||
Valid contradictory evidence (Y/N)*
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CALCULATED CLASSIFICATION (DATE) |
No Classification
07/24/2018
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MODIFY CALCULATED CLASSIFICATION |
YES
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MODIFIED CLASSIFICATION (DATE) |
Disputed
07/24/2018
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REASON(S) FOR CHANGE |
no score-able cases
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EXPERT CURATION (DATE) |
Disputed
07/24/2018
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EVIDENCE SUMMARY |
There have been five studies to date that have identified patients with features consistent with Costello syndrome (CS) and de novo or inherited variants in KRAS (Carta et al., 2006; Nava et al., 2007; Schubbert et al., 2007; Zenker et al., 2007). However, none of the patients possessed features to definitively differentiate their diagnosis from other RASopathies as CS. Variable expressivity, age of ascertainment, and outdated clinical assessments of affected individuals may complicate the clinical diagnosis of CS versus severe forms of CFC. Therefore, the evidence for this association is Disputed. Furthermore, the HRAS gene is believed to be the only gene associated with CS (Aoki et al., 2005; Estep, Tidyman, Teitell, Cotter, & Rauen, 2006; Gripp et al., 2006; Kerr et al., 2006; Zampino et al., 2007).
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