ClinGen Dosage Sensitivity Curation Page

COL4A5

Curation Status: Complete

Gene Information

Location Information

Evidence for Loss Phenotypes

Evidence for loss of function phenotype
PubMed ID Description
16941480 King et al (2006) sequenced the COL4A5 gene in 25 unrelated patients with clear Alport syndrome and identified 21 mutations including 4 exon level deletions (del exons 2-37; del exons 31-36; del exons 35-36; del exons 46-51), 3 frameshifts (c.2510delG, c.2_3delTG, c.2846delC), 2 canonical splice site mutations (c.1780-1G>A, c.2244+2T>C). Therefore, a total of 9 LOF variants identified in 9 patients with Alport syndrome.
10752524 Jais et al (2000) 401 male patients with Alport syndrome in 195 families with COL4A5 mutation were reported. Among those, 37 frameshift mutations, 14 nonsense mutations were identified.
30577881 Zhang et al (2018) All 87 patients with Alport syndrome were tested for COL4A5/6 genotype, where 60 different COL4A5 pathogenic variants were identified in 63 patients, including 10 frameshifts, 5 nonsense (p.Arg373*, p.Lys1284*; p.Arg1680*, p.Ser36*, p.G1360*).

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.

Evidence for Triplosenstive Phenotype

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.

NOTE:The loss of function score should be used to evaluate deletions, and the triplosensitivity score should be used to evaluated duplications. CNVs encompassing more than one gene must be evaluated in their totality (e.g. overall size, gain vs. loss, presence of other genes, etc). The rating of a single gene within the CNV should not necessarily be the only criteria by which one defines a clinical interpretation. Individual interpretations must take into account the phenotype described for the patient as well as issues of penetrance and expressivity of the disorder. ACMG has published guidelines for the characterization of postnatal CNVs, and these recommendations should be utilized (Genet Med (2011)13: 680-685). Exceptions to these interpretive correlations will occur, and clinical judgment should always be exercised.