ClinVar Miner

Submissions for variant NM_000039.2(APOA1):c.181G>A (p.Ala61Thr) (rs12718465)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000335636 SCV000367383 likely benign Familial High Density Lipoprotein Deficiency 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000395998 SCV000367384 likely benign Familial visceral amyloidosis, Ostertag type 2016-06-14 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America 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.

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