ClinVar Genomic variation as it relates to human health

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Variant summary: APOA1 c.284T>A (p.Phe95Tyr) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00052 in 251392 control chromosomes, predominantly at a frequency of 0.0013 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 52 fold of the estimated maximal expected allele frequency for a pathogenic variant in APOA1 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.284T>A has been reported in the literature in one individual affected with apolipoprotein A-I amyloidosis and individuals with lower than average apoA-I and HDL cholesterol levels (Rowczenio_2011, Haase_2012). These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. At least two publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Das_2016, Morgado_2018). One ClinVar submitter (evaluation after 2014) cites the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.

This sequence change replaces phenylalanine, which is neutral and non-polar, with tyrosine, which is neutral and polar, at codon 95 of the APOA1 protein (p.Phe95Tyr). This variant is present in population databases (rs138407155, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with amyloidosis or low HDL-cholesterol (PMID: 21820994, 24081495). This variant is also known as Phe71Tyr. ClinVar contains an entry for this variant (Variation ID: 302506). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt APOA1 protein function with a positive predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on APOA1 function (PMID: 30184436). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Functional studies show this variant may lead to changes in protein conformation and stability but less so than other known APOA1 variants (PMID: 30184436, 26562506); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as F71Y; This variant is associated with the following publications: (PMID: 26562506, 23806608, 23209431, 34426522, 24081495, 30184436, 21820994, 32041611, 38112957, 30476936)