Submissions for variant NM_000039.3(APOA1):c.181G>A (p.Ala61Thr)

gnomAD frequency: 0.00091  dbSNP: rs12718465

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000335636	SCV000367383	benign	Hypoalphalipoproteinemia, primary, 1	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Illumina Laboratory Services, Illumina	RCV000395998	SCV000367384	benign	Familial visceral amyloidosis, Ostertag type	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000779744	SCV000916518	benign	not specified	2018-10-29	criteria provided, single submitter	clinical testing	Variant summary: APOA1 c.181G>A (p.Ala61Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0028 in 277088 control chromosomes, predominantly at a frequency of 0.04 within the East Asian subpopulation in the gnomAD database, including 13 homozygotes. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 4000 fold of the estimated maximal expected allele frequency for a pathogenic variant in APOA1 causing Apoliprotein A1 Amyloidosis phenotype (1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.181G>A has been reported in the literature in individuals affected with Apoliprotein A1 deficiency, familial hypercholesterolemia, and Moyamoya disease (Matsunaga_1991, Pek_2017, Shoemaker_2015). These reports do not provide unequivocal conclusions about association of the variant with Apoliprotein A1 Amyloidosis, Apolipoprotein-A1 deficiency or familial hypercholestrolemia. Co-occurrences with other pathogenic variant(s) have been reported (APOA1 c.322C>T, p.Gln108X) in a female patient with apolipoprotein A-I deficiency, providing supporting evidence for a benign role (Matsunaga_1991). In addition, six control individuals who carry this variant showed normal plasma HDL cholesterol and apoA-I (Matsunaga_1991). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000892083	SCV001035938	benign	not provided	2024-01-26	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000779744	SCV002064928	benign	not specified	2021-03-19	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000395998	SCV002539393	benign	Familial visceral amyloidosis, Ostertag type	2021-12-05	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002259800	SCV002539394	benign	Hypoalphalipoproteinemia, primary, 2	2021-12-05	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002259801	SCV002539395	benign	Hypoalphalipoproteinemia, primary, 2, intermediate	2021-12-05	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002411194	SCV002710418	benign	Cardiovascular phenotype	2020-01-23	criteria provided, single submitter	clinical testing	This alteration is classified as 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.