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C5AR2 and Familial Combined Hyperlipidemia

The association between C5AR2 (HGNC:4527) and familial combined hyperlipidemia (MONDO_0007759) was initially reported in a French Canadian family where a heterozygous variant, c.968G>T (p.Ser323Ile) (PMID:16627811), co‑segregated with dyslipidemia. In this study, the variant was identified in one proband and was present in eight additional affected relatives (PMID:16627811), providing preliminary genetic evidence for its involvement in the disorder.

Although the genetic data suggest a potential role for C5AR2 in familial combined hyperlipidemia, a subsequent analysis in a Chinese cohort found no instances of the c.968G>T (p.Ser323Ile) variant in patients with familial combined hyperlipidemia or type 2 diabetes (PMID:22194190). In contrast, functional studies consistently demonstrated that the S323I alteration substantially impairs receptor function by causing a 50% reduction in ASP-mediated triglyceride synthesis, glucose transport, and reduced receptor binding (PMID:16627811; PMID:19615750). Together, these findings highlight that while there is solid functional support for a deleterious effect of the variant, the genetic evidence remains limited due to its isolation to a single family and lack of replication.

Key take‑home sentence: The c.968G>T (p.Ser323Ile) variant in C5AR2 may contribute to familial combined hyperlipidemia, but further corroborative clinical data are required to enhance its diagnostic utility.

References

  • Arteriosclerosis, thrombosis, and vascular biology • 2006 • Identification of a novel C5L2 variant (S323I) in a French Canadian family with familial combined hyperlipemia PMID:16627811
  • Genetics and molecular research : GMR • 2011 • S323I polymorphism of the C5L2 gene was not identified in a Chinese population with familial combined hyperlipidemia or with type 2 diabetes PMID:22194190
  • Molecular immunology • 2009 • C5a- and ASP-mediated C5L2 activation, endocytosis and recycling are lost in S323I-C5L2 mutation PMID:19615750

Evidence Based Scoring (AI generated)

Gene–Disease Association

Limited

The association is based on a single proband with segregation in eight affected relatives (PMID:16627811) and is weakened by the lack of replication in an independent Chinese cohort (PMID:22194190).

Genetic Evidence

Limited

Only one heterozygous variant, c.968G>T (p.Ser323Ile), was reported in a single family with familial combined hyperlipidemia, supported by segregation in eight additional relatives (PMID:16627811).

Functional Evidence

Moderate

Robust in vitro assays demonstrated a 50% reduction in ASP-mediated triglyceride synthesis, impaired glucose transport, and reduced receptor binding for the S323I variant (PMID:16627811; PMID:19615750), supporting its functional impact.