COL4A5

• Haploinsufficiency score: 3
• Strength of Evidence (disclaimer): Sufficient evidence for dosage pathogenicity
• Haploinsufficiency Phenotype: ALPORT SYNDROME 1, X-LINKED; ATS1

Evidence for haploinsufficiency 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*).

Haploinsufficiency phenotype comments:

About 85% of Alport syndrome is caused by mutations in the collagen gene, COL4A5. 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.

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.

• Triplosensitivity score: 0
• Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

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.