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PMID: 37644014 in family F7988. Variant is homozygous which doesn’t fit proposed inheritance. Per supplement data 1, phenotype is Supernumerary nipple; Supernumerary ribs; Dextrocardia; Abnormal facial shape; Abnormal heart morphology (complex heart disease); Pulmonary situs ambiguus; Asplenia; midline liver; Bilateral talipes equinovarus; Hypoplasia of the corpus callosum; Wide anterior fontanel; Micrognathia. There was no further segregation / variant information provided. 0.5 POINTS FOR AR
NM_001106.4: c.119G>A; p.R40H - frequency too high in gnomAD, did not score papers. 1.2% in AA (963/75038) with 12 homozygotes. 2 star B/LB in ClinVar.
PMID: 30293987 - variant reported in patient with congenital heart diease but also found in asymptomatic mother (family 150650086). This proband also had a HOM variant in DOCK6 (AR Adams-Oliver syndrome, which has CHD. No points can be applied for this family given the alternate explanation of disease.
NM_001106.4:c.1480G>A p.V494I - 14 alleles gnomAD v4 [0.0005% (12/1180020] European non-FInnish chr.
REVEL: 0.374
PMID: 9916847 - cant access, but per OMIM in a patient with left-right axis malformation. 0.5 points for AD.
NM_001106.4: c.925C>T Arg309Cys (DM? in HGMD), frequency in gAD higher than expected for AD, 0.002% (5/91080) S. Asian, also present in other populations. REVEL: 0.594
PMID:35547246Found in patient w/ laterality defect, but Patient also HOMOZYGOUS c.350A>G p.Asp117Gly in CCDC39. no points
PMID: 30622330 - this paper had several variant marked as DM?
NM_001106.4:c.1147C>T NP_001097.2:p.Arg383Cys - absent gnomAD. Family ID: LAT1543 Observed in patient w/ laterality defect and segregated in 4 affected family members. The diagnosis in the proband was a venous anomaly per table 1, but reviewing supplement 1 the proband had atrial septal defect, Interrupted IVC, TAPV. “Left superior vena cava to coronary sinus, MR,PR, TR, Right ventricular hypertrophy, Right ventricular dilation or enlargement, Dilatation of the main pulmonary artery Unusual systemic venous return from the lower extremities and abdomen with a small (b”. AD EVIDENCE: 0.5 VARIANT POINT, 4 AD SEGREGATION (0 SEGREGATION POINTS)
NM_001106.4:c.527C>G P176R in a patient w/ conotruncal defect per table 1, in LAT1333. Per table s1, DORV with the PA arising slightly more anterior than the aorta. BILATERAL GRADE IV VESICOURETERAL REFLUX. but frequency looks too high with 479/1180000 alleles in gAD v4 European chr. gnomAD . No
Mouse:
Targeted disruption of mouse Acvr2b gene results in abnormal left-right developments in homozygous knockout. PMID: 9242489. SCORE 2 POINTS AR, 1 POINT FOR AD
A knockout mouse of Pitx2, the downstream targeted of Acvr2b, showed an identical phenotype to Acvr2b homozygous knockout mouse PMID: 10499586. Scoring under protein interaction. 1 POINT FOR AR, 0.5 POINT FOR AD.
Pubmed search:
no additional papers found to curate
Clinical ValidityPoints Total
AD EVIDENCE: 2.5 POINTS
AR EVIDENCE: 3.5 POINTS
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