IN PROGRESS COL4A1 Gene Curation
- Andrea Oza
Analytics
Gene-disease assertions not curated here (add link or write note):
LUMPING / SPLITTING
Many conditions in HGMD, in scope for 5 different GCEPs. Curating this for NM_001845.6(COL4A1): c.4721G>A p.Trp1574Ter
Disease | COL4A1-related small vessel brain disease |
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Inheritance | Autosomal dominant |
Prevalence |
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Rapid or full curation? | Rapid Full |
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Clinical Validity Scoring Notes and points |
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Clinical Validity Points Total |
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Clinical Validity Classification Definitive (12pts) Strong (12pts) Moderate (7-11pts) Limited (0.1-6pts) No genetic evidence Refuted Disputed |
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Molecular Mechanism Loss of function Gain of function Dominant negative Unknown Other | Loss of function / Gain of function / Dominant Negative Gene is highly constrained for LOF variants with LOEUF 0.128
PMID: 32732225 - Several truncating variants shown in table 1. [[1]] c.2539del p.(Ala847Leufs*7) absent gnomAD, expected to undergo NMD, inherited from mother, proband with leukoenceophalopathy. 2 POINTS [[2]]c.3628G>T p.(Gly1210*) - absent gnomAD, de novo, NMD+, phenotype is porencephaly, no prenatal findings. 2.5 POINTS [[3]] c.4875C>A p.Y1625* - just barely on the cusp of undergoing NMD. Absent gnomAD. 2 POINTS[[4]] c.3024del p.Gly1009Valfs*58 - prenatal finidngs include ventriculomegaly, fetal growth restriction, cerebral hemorrhage. Dx with porencephaly postnatally. NMD+ and absent gnomAD. 2 POINTS. TOTAL = 8.5 POINTS VARIANT/CASE POINTS, ALL LOF variants c.4887C>A p.Y1629* - not expected to undergo NMD. Did not review for now PMID: 33532864 - c.1937delG p.(Gly646Alafs*156) - PTC occurs at aa 802, expected to undergo NMD. See supplement for the variant. Found in a patient with a diagnosis of UGLO (unspecified glomerulopathy) with age of onset at 15 years. Since the phenotype here is not specific, I am not scoring this case. PMID: 23065703 c.2085delC p.(Gly696Alafs*106) - absent gnomAD, NMD+, variant found in family A (see fig 1a for pedigree). Per text it was found in three affected individuals. Proband II:1 had intrancranial hemorrhage, the daughter III:1 with porencephaly and in I:2 with white matter disease. Text describes features in proband. 2 SEGREGATIONS, 2 VARIANT/CASE POINTS PMID: 34374989 c.3880_3881delAT p.(Ile1294Trpfs*10) - NMD+ and absent from gnomAD. Found de novo patient 5 with DD/seizures/muscle weakness/abnormal MRI brain (table 3). This isn’t specific enough to score. |
Penetrance Complete (100%) High (≥80%) Moderate (<80% and >20%) Low (≤20%) (list source/PMID) |
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Age of Onset Congenital Pediatric Adolescent Adulthood Late adulthood (list source/PMID) |
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Severity |
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Clinical Features |
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HPO Terms |
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Gene SOPs & Notes | LINK if SOP is a long document. Short notes if it is easy to digest. eg. Last known truncating variant |
Curation Summary |
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Case ID, Curator name, Date, Jira ticket link |
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