Proteinuria

Gene: ACTN4

Green List (high evidence)

PTC variants: Uncertain mechanism– no reported PTCs. However pLI = 1, and knockout homozygous mice demonstrated a lethal, severe phenotype (PMID: 26301083). Based on the KO data and pLI, HOM LoF are likely lethal and therefore not seen in patients. According to animal models and experiments described in Feng, D. et al. (2015) review, no data to supports LoF in HET yet. Missense variants: Suggested GOF and DN. LoF is possible. Kaplan (2000): mutant protein coprecipitated at greater quantities with F-actin than wildtype -> increased binding ability (GOF) Khurana (2012): mutant missense protein mislocalized when expressed with wildtype protein, and prevented transcriptional activation of RARa (DN). Caution as one of the variants they study is (p.S235P), was shown by to cause GoF. Bartram (2016): mutant missense protein mislocalization with aggregates formed, reduced protein stability (GOF) ClinVar: 6 miss only

Created: 17 Aug 2020, 2:54 a.m. | Last Modified: 17 Aug 2020, 2:54 a.m.

Panel Version: 0.112

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Glomerulosclerosis, focal segmental, 1, MIM#603278

Publications

• 26740551
• 22351778
• 10700177
• 26301083

Green List (high evidence)

PTC variants: Uncertain mechanism– no reported PTCs. However pLI = 1, and knockout homozygous mice demonstrated a lethal, severe phenotype (PMID: 26301083). Based on the KO data and pLI, HOM LoF are likely lethal and therefore not seen in patients. According to animal models and experiments described in Feng, D. et al. (2015) review, no data to supports LoF in HET yet.

Missense variants: Suggested GOF and DN. LoF is possible.
Kaplan (2000): mutant protein coprecipitated at greater quantities with F-actin than wildtype -> increased binding ability (GOF)
Khurana (2012): mutant missense protein mislocalized when expressed with wildtype protein, and prevented transcriptional activation of RARa (DN). Caution as one of the variants they study is (p.S235P), was shown by to cause GoF.
Bartram (2016): mutant missense protein mislocalization with aggregates formed, reduced protein stability (GOF)
ClinVar: 6 miss only

Created: 16 Aug 2020, 11:07 p.m. | Last Modified: 16 Aug 2020, 11:07 p.m.

Panel Version: 0.3806

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Glomerulosclerosis, focal segmental, 1, 603278

Publications

• PMID: 26740551
• 22351778
• 10700177
• 26301083

Mode of pathogenicity
Other