Table 2 Evidence for classification of the CLCN5 c.1744_1745delinsAA p.(Ala582Lys) variant using ACMG and ACGS guidelines [5, 8]
From: A novel likely pathogenic CLCN5 variant in Dent’s disease
Criteria code weight | Pathogenic evidence |
|---|---|
PS4 Supporting | The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls. The variant was identified in unrelated index patients affected with X-linked Dent disease in the Bristol Genetics Laboratory. |
PM2 Moderate | Absent from controls (or at extremely low frequency if recessive). Not recorded on the population database gnomAD. |
PP1 Supporting | Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease. Observed segregating in at least three informative meioses in a family. |
PP3 Supporting | Multiple lines of computational evidence support a deleterious effect on the gene or gene product. Polyphen: Probably damaging; SIFT: Deleterious; Splicing prediction tools: No effect; Align AGVD: C65; Amino acid conservation: High. |
PP4 Supporting | Patient’s phenotype or family history is highly specific for a disease with a limited number of genetic aetiologies. The second index patient with this variant is reported to have clinical Dent’s disease, which is distinctly associated with the CLCN5 gene, where other known genetic aetiologies have been excluded. |
Summary | 1x Moderate and 4x Supporting = Likely pathogenic |