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 rule this variant out of causing disease. Therefore, this variant is classified as 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 rule this variant out of causing disease. Therefore, this variant is classified as benign.

This sequence change replaces serine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 60 of the APOA1 protein (p.Ser60Ala). This variant is present in population databases (rs199759119, gnomAD 0.06%). This missense change has been observed in individual(s) with APOA1-related disease (PMID: 17303779, 20884842, 21820994, 30333156, 32041611). This variant is also known as S36A. ClinVar contains an entry for this variant (Variation ID: 879223). 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 have shown that this missense change affects APOA1 function (PMID: 20884842). 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.

Variant summary: APOA1 c.178T>G (p.Ser60Ala) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00068 in 1614034 control chromosomes in the gnomAD database, including 2 homozygotes. c.178T>G (also known as S36A) has been reported in the literature in individuals affected with APOA1-Related Disorders and individuals from low level high-density lipoprotein cholesterol (HDL-C)cohort studies (examples: Kiss_2007, Weers_2011, Rowcenio_2011, Haase_2012, Morrison_2013, Morrison_2013, Geller_2018, Dron_2020, Dong_2022). These report(s) do not provide unequivocal conclusions about association of the variant with APOA1-Related Disorders. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Weers_2011). The following publications have been ascertained in the context of this evaluation (PMID: 32041611, 25972569, 35460704, 30333156, 17303779, 23770607, 21820994, 20884842). ClinVar contains an entry for this variant (Variation ID: 879223). Based on the evidence outlined above, the variant was classified as 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.

Published functional studies suggest a damaging effect on APOA1 activity (PMID: 20884842); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 17303779, 21820994, 23209431, 23770607, 30333156, 34426522, 20884842, 32041611)