ClinVar Miner

Submissions for variant NM_000039.3(APOA1):c.296T>C (p.Leu99Pro)

gnomAD frequency: 0.00001  dbSNP: rs372520221
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Mayo Clinic Laboratories, Mayo Clinic RCV001508676 SCV001714992 pathogenic not provided 2023-07-28 criteria provided, single submitter clinical testing PP4, PS3, PS4
Labcorp Genetics (formerly Invitae), Labcorp RCV001508676 SCV002239472 pathogenic not provided 2024-12-22 criteria provided, single submitter clinical testing This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 99 of the APOA1 protein (p.Leu99Pro). This variant is present in population databases (rs372520221, gnomAD 0.002%). This missense change has been observed in individual(s) with APOA1-related amyloidosis and/or autosomal dominant APOA1-related amyloidosis (PMID: 14986480, 15131802, 21458433, 24650283, 26193960). It has also been observed to segregate with disease in related individuals. This variant is also known as Leu75Pro. ClinVar contains an entry for this variant (Variation ID: 1163527). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt APOA1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects APOA1 function (PMID: 21296086, 24603325, 26515634). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV002439206 SCV002746179 likely pathogenic Cardiovascular phenotype 2020-08-11 criteria provided, single submitter clinical testing The p.L99P variant (also known as c.296T>C), located in coding exon 3 of the APOA1 gene, results from a T to C substitution at nucleotide position 296. The leucine at codon 99 is replaced by proline, an amino acid with similar properties. This variant has been identified in several individuals with hepatic amyloidoses in multiple unrelated families (Coriu D et al. Amyloid, 2003 Dec;10:215-23; Obici L et al. Gastroenterology, 2004 May;126:1416-22; Eriksson M et al. J Mol Diagn, 2009 May;11:257-62). Individuals with this variant may have reduced levels of total cholesterol and high-density lipoprotein cholesterol (HDL-C) (Muiesan ML et al. Amyloid, 2015 Jul;22:187-93; Gomaraschi M et al. Clin. Chim. Acta, 2011 Jun;412:1262-5). In addition to the clinical data presented in the literature, protein aggregation and cell survival assays indicate that this alteration is functionally abnormal (Raimondi S et al. J. Mol. Biol., 2011 Apr;407:465-76; Del Giudice R et al. Cell Death Dis, 2014 Mar;5:e1097).This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Fulgent Genetics, Fulgent Genetics RCV005040302 SCV005680697 pathogenic Familial amyloid polyneuropathy, Iowa type; Hypoalphalipoproteinemia, primary, 2; Hypoalphalipoproteinemia, primary, 2, intermediate 2024-03-04 criteria provided, single submitter clinical testing

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