Lipodystrophy - childhood onsetGene: CAV1
Comment on list classification: New gene added by reviewer. After reviewing the evidence provided by the expert reviewer, it was decided that there is enough evidence to promote this gene from amber to green.
It should be noted that causative variants might only be those that are either homozygous null variants or heterozygous variants that causes truncated protein to be made.
Created: 5 Jul 2019, 12:32 p.m. | Last Modified: 5 Jul 2019, 12:32 p.m.
Panel Version: 1.7
Id initially classified as green but I think this is more complex due to the fact that there are reports of both dominant and recessively inherited variants causing different phenotypes.I think there is a genotype-phenotype association here, and I dont think haploinsufficiency is a disease mechanism since individuals with heterozygous loss of protein expression do not have a lipodystrophy phenotype (whole gene deletion patients and the heterozygous parents with p.Glu38Ter).All other reported variants are within the last exon and are expected to escape nonsense mediated decay, generating a truncated protein or a full length protein with an altered C-terminal sequence. The p.(Phe160Ter) variant looks to be a definite CGL causing variant. Then there are two other PTC variants resulting in a shorter protein with a lipodystrophy phenotype. And finally two patients with very similar frameshift variants that result in full-length proteins with altered C-terminal amino acid sequence. So it could be that only homozygous null variants or heterozygous variants that result in a truncated protein are causing a lipodystrophy phenotype.
Created: 5 Jul 2019, 9:50 a.m. | Last Modified: 5 Jul 2019, 9:50 a.m.
Panel Version: 1.6
5 different loss of function variants have been reported in CAV1 to date associated with a lipodystrophy phenotype. No missense variants reported. GnomAD pLi score of 0.67 does not suggest that CAV1 is intolerant to loss of function variants.
Both heterozygous and homozygous LoF variants have been reported in patients with congenital lipodystrophy (PMID: 18211975, 25898808, 18237401).
A heterozygous c.-88del variant within the 5'UTR was identified in a patient with adult-onset partial lipodystrophy but with no proposed mechanism for a pathogenic effect on CAV1 (PMID: 18237401; the authors incorrectly described this a frameshift variant).
Frameshift variants within the C-terminal region of the gene that are predicted to escape NMD have been reported in patients with PAH but no lipodystrophy phenotype (PMID: 22474227).
Created: 26 Jun 2019, 3:45 p.m. | Last Modified: 26 Jun 2019, 3:45 p.m.
Panel Version: 1.3
Sources: Expert Review
Created: 26 Jun 2019, 3:05 p.m.
Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal
?Lipodystrophy, congenital generalized, type 3, 612526; Lipodystrophy, familial partial, type 7, 606721
Variants in this GENE are reported as part of current diagnostic practice
Gene: cav1 has been classified as Green List (High Evidence).
Phenotypes for gene: CAV1 were changed from ?Lipodystrophy, congenital generalized, type 3, 612526 to ?Lipodystrophy, congenital generalized, type 3, 612526; Lipodystrophy, familial partial, type 7, 606721
Publications for gene: CAV1 were set to PMID: 18390817; 18237401; 18211975; 25898808; 26176221; 27717241; 11739396; 23049990
gene: CAV1 was added gene: CAV1 was added to Lipodystrophy - childhood onset. Sources: Expert Review Mode of inheritance for gene: CAV1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: CAV1 were set to PMID: 18390817; 18237401; 18211975; 25898808; 26176221; 27717241; 11739396; 23049990 Phenotypes for gene: CAV1 were set to ?Lipodystrophy, congenital generalized, type 3, 612526 Penetrance for gene: CAV1 were set to Complete Review for gene: CAV1 was set to AMBER gene: CAV1 was marked as current diagnostic