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Not in ClinGen, GenCC, babySeq. Curated HGMD variants below.
Clinical Validity Scoring Notes and points
Gene is not constrained for missense or pLOF variants. All of the variants in HGMD are in gnomAD (see each one below). I scored these generously despite the MAF, but you could argue that some of the variants I scored should not get any points at all. Scored VSD as common phenotype, but TOF or complex CHD such as coarctation as rare phenotype.
Werner 2016 PMID: 26694203
c.79_87dup9 p.P27_D29dup - 0.001% (20/1011174) European chr, gAD v4. CADD: 9.95. in a patient with conoventricular VSD, inherited from father. Common phenotype 0.1 point, but not scoring due to MAF.
c.310G>A p.E104K - 0.004% (65/1117728) European chr in gAD v4. REVEL score 0.386. Found in a patient with tetrology of Fallot, inherited from mother per table 2. Downgrading due to MAF to 0.1 point
c.359T>C p.L120P - 0.3% (144/37088) East Asian in gAD v4. REVEL 0.88. in a patient with conoventricular VSD. No points, MAF too high.
c.436_437delAG p.L147Pfs*9 - 0.017% (19/69736) African/African American alleles gAD v4, NMD+ in a patient with conoventricular VSD. 1 point for common phenotype (VSD), downgrading to 0.5 due to MAF. 0.5 point
c.503A>G p.D168G - in patient with conoventricular VSD. 2.7% (1929/67414) African/African American alleles gAD v4. Did not score, MAF too high.
c.804G>C p.K268N - in patient with VSD, coarctation of aorta, aortic atresia. Inherited from mom. 0.0005% (2/60016) Admixed American gAD v4. REVEL 0.177 0.5 point
Zhang 2017 PMID: 28677747
c.352C>T p.Q118* - 2 alleles gnomAD, but covered in <50% of individuals in exome data. NMD+ in a patient with double outlet right ventricle and a VSD. They performed Sanger sequencing for MESP1 only. Parents were negative, variant was reported de novo. A dual luciferace reporter assay had reduced activation when expressed alone, but looking at fig 4 when co-expresse with wt it doesn’t look like there was a difference between wt-Q118X and wt-MESP1 alone. Downgrading to 1 point due to coverage in gnomAD and only Sanger performed, but adding 0.5 for de novo 1.5 POINTS
c.370G>T p.E124* - 0.004% (32/1143200) European non-Finnish alleles gnomAD. In a patient with TOF. NMD+. 2 point, but downgrading to 1 due to MAF. 1 POINT
Clinical ValidityPoints Total
3.6
Clinical ValidityClassification
Definitive (12pts)
Strong (12pts)
Moderate (7-11pts)
Limited (0.1-6pts)
No genetic evidence
Refuted
Disputed
Limited
MolecularMechanism
Loss of function
Gain of function
Dominant negative
Unknown
Other
Loss of function / Gain of function / Dominant Negative
Penetrance
Complete (100%)
High (≥80%)
Moderate (<80% and >20%)
Low (≤20%)
(list source/PMID)
Source:
Age of Onset
Congenital
Pediatric
Adolescent
Adulthood
Late adulthood
(list source/PMID)
Severity
Embryonic lethal - presence of a pathogenic variant or variants is not compatible with life. The penetrance must be complete. Severe - presence of a pathogenic variant or variant(s) results in significantly reduced fitness. The penetrance must be complete or high. Moderate - significant morbidity or mortality due to clinical features, but fitness may not be reduced, or penetrance is reduced. Mild - Presence of a variant or variant(s) is not associated with reduced fitness, no significant morbidity or mortality, and/or penetrance is low. None - presence of a variant results in no phenotype. An example is recessive disorders in which no phenotype is reported in carriers.
LINK if SOP is a long document. Short notes if it is easy to digest. eg. Last known truncating variant
Curation Summary
- The @GENE@ is associated with @inheritance pattern@ @condition@, which is characterized by @clinical features@ (PMIDs).
- Variable expression or severity: The severity and expressivity of the disorder is highly variable, even within families. - If multiple conditions associated with the gene: It has also been associated with @inheritance pattern@ @condition@, which is characterized by @clinical features@ (PMIDs).
- Limited evidence gene: The PCNA gene has been reported in individuals with early onset autosomal recessive ataxia (PMID: 33426167, 24911150), however, evidence supporting this gene-dIsease relationship is limited