Clinical Validity Scoring Notes and points | NM_138576.4: c.2346_2361del, p.(Gly783Alafs*24) - 1.5 points Zhao et al, 2022, PMID: 36275064: 25 month old Chinese male w/ craniosynostosis, global developmental delay (ID, speech impairment, motor delay, abnormal brain MRI), small mouth, thin upper lip, arched eyebrows, a long philtrum, midfacial hypoplasia, increased IgE. Identified by whole exome sequencing. De novo determined by Sanger sequencing. 1 point (common, NMD-, de novo). Occurs in exon 4/4, NMD is not predicted. 111/894 amino acids removed (12.4%). Present in 1 allele in gnomAD v4. P in ClinVar by Children’s Hospital of Fudan University (same as PMID: 36275064) and University Hospital Muenster. Both submissions state that the individual was affected and that the variant was de novo. The submission from UHM says that this was a 10-19yo male with Global developmental delay, Trigonocephaly (subtype of craniosynostosis), Obesity, Sleep abnormality, EEG abnormality, Impulsivity. 0.5 points (common, NMD-, de novo, removed 0.5 points due to lack of information about how the variant was ascertained).
NM_138576.4(BCL11B_v001): c.2439_2452dup [p.(His818Argfs*31)] - 1 point Eto et al, 2022, PMID: 36470856: 5 yo Japanese male with developmental delay, early craniosynostosis, and distinctive features including forehead protrusion, arched eyebrows, flat nose base, thin upper lip, small mouth, long philtrum, retrognathia and low-set ears. Patient also had feeding issues. Variant identified on trio exome sequencing and confirmed by Sanger. 1 point (common, NMD-, de novo). Occurs in exon 4/4, NMD is not predicted. 76/894 amino acids removed (8.5%). Absent from gnomAD v4. LP/VUS in ClinVar by Baylor and Invitae, respectively. Baylor reports patient was affected and variant was de novo, but no clinical features reported.
BCL11B (NM_138576.4) c.2605del p.(Leu869TrpfsTer5) - 1 point Pande et al, 2023 PMID: 37337996: 1yo female with sagittal suture craniosynostosis and dysmorphic features including low posterior hairline, scaphocephaly, tall forehead, small and down-slanting palpebral fissures, telecanthus, depressed nasal root with convex nasal bridge, low set and anteverted external ears, small earlobes, long and smooth philtrum, thin upper vermilion and a small mouth. She also had microcytic hypochromic anemia and a normal MRI. Variant was identified on trio exome and confirmed de novo, confirmed by Sanger sequencing. 1 point (common, NMD-, de novo). Occurs in exon 4/4, NMD is not predicted. 25/894 amino acids removed (2.8%) Absent from GnomAD v4. P in ClinVar by authors of PMID: 37337996.
BCL11B (NM_138576.4) c.1662_1668del p.(Ser555AlafsTer6) - 0 points Pande et al, 2023 PMID: 37337996: 10 month old female with abnormal head shape with brachycephaly, prominent metopic suture and mild proptosis suggestive of craniosynostosis. She also had microcephaly, mid-face retrusion, high arched palate, hirsutism, hypodontia, umbilical hernia and mild hepatomegaly. Pt died at 12 months old due to lower respiratory tract infection with high-grade fever. Variant was identified on trio exome sequencing and confirmed by Sanger, de novo. Pt also carried two other de novo heterozygous variants, c.881G>A p.(Arg294Gln) in exon 10 of KRIT1 (NM_194454.3) and c.328C>Tp.(Arg110Cys) in exon 6 of MORC2 (NM_001303256.3). Authors considered both likely pathogenic. Not scoring this patient due to the presence of other variants. Occurs in exon 4/4, NMD not predicted, 339/894 amino acids removed (37.9%)
BCL11B (NM_138576.4) c.2443del p.(Arg815GlyfsTer29) - 1 point Pande et al, 2023 PMID: 37337996: 5 yo male with premature fusion of sagittal suture suggestive of sagittal suture craniosynostosis, ventricular cyst in brain, papular rashes, developmental delay, normochromic normocytic anemia, elevated IgE, abnormal brain MRI, scaphocephaly, tall forehead, low set ears with small ear lobes, high bridge of nose with overhanging columella, long philtrum, thin upper and lower vermillion borders and downturned corners of mouth. Normal microarray. Variant identified on singleton exome sequencing, confirmed de novo by Sanger. 1 point (common, NMD-, de novo). Occurs in exon 4/4, NMD is not predicted. 79/894 amino acids removed (8.8%) Absent from GnomAD v4. P in ClinVar by authors of PMID: 37337996.
BCL11B c.7C>A p.Arg3Ser - 1.1 points Goos et al 2019, PMID: 31067316: Now 19yo male patient with craniosynostosis, dysmorphic features, impaired vision, seizures, but otherwise healthy and did not present with any extra-craniofacial pathologies. Variant identified by trio WGS, de novo. Authors showed that mice with this variant developed variable and partial, bilateral osteogenic fusion of the coronal suture that was accompanied by narrowing of the sagittal and lambdoid sutures. Homozygous, mutant mice (Bcl11bR3S/R3S) recapitulated perinatal lethality of of Bcl11b−/− mice due to apparent respiratory insufficiency. 1.1 points (missense variant, common, functional data, de novo). Absent from gnomAD v4. Absent from ClinVar.
Additional variants not included here: Functional studies: PMID: 38472338 - review paper Variant/Case Evidence: 5.6 points Segregation Evidence: Case/Control Evidence: Experimental Evidence: 2 points Source: |