Submissions for variant NM_000039.3(APOA1):c.732C>G (p.Pro244=)

gnomAD frequency: 0.00368  dbSNP: rs5080

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000368370	SCV000367372	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.
Illumina Laboratory Services, Illumina	RCV000271540	SCV000367373	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000779742	SCV000916516	benign	not specified	2018-08-14	criteria provided, single submitter	clinical testing	Variant summary: APOA1 c.732C>G alters a non-conserved nucleotide resulting in a synonymous change. Several computational tools predict a significant impact on normal splicing: Three predict the variant creates a cryptic 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0012 in 275838 control chromosomes, predominantly at a frequency of 0.011 within the African subpopulation in the gnomAD database, including 4 homozygotes. The observed variant frequency within African control individuals in the gnomAD database is approximately 440-folds higher than 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 African origin. A publication cites the variant in a cohort from the Copenhagen City Heart Study (Haase_2012), but with limitied information. A ClinVar submission from another clinical diagnostic laboratory (evaluation after 2014) cite the variant as "likely benign." Based on the evidence outlined above, the variant was classified as benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000905548	SCV001050135	benign	not provided	2025-01-27	criteria provided, single submitter	clinical testing
GeneDx	RCV000905548	SCV001777358	likely benign	not provided	2021-03-15	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000368370	SCV002539383	benign	Familial visceral amyloidosis, Ostertag type	2021-12-05	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002259798	SCV002539384	benign	Hypoalphalipoproteinemia, primary, 2	2021-12-05	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002259799	SCV002539386	benign	Hypoalphalipoproteinemia, primary, 2, intermediate	2021-12-05	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002379172	SCV002671061	benign	Cardiovascular phenotype	2021-12-21	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.
Breakthrough Genomics, Breakthrough Genomics	RCV000905548	SCV005217984	likely benign	not provided		criteria provided, single submitter	not provided
Genetic Services Laboratory, University of Chicago	RCV000779742	SCV003839770	likely benign	not specified	2022-07-27	no assertion criteria provided	clinical testing