Submissions for variant NM_001371904.1(APOA5):c.823C>T (p.Gln275Ter)

gnomAD frequency: 0.00004  dbSNP: rs149808404

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001570903	SCV001795275	pathogenic	not provided	2022-12-08	criteria provided, single submitter	clinical testing	Identified in at least two unrelated individuals with hypertriglyceridemia who also harbored other variants in dyslipidemia-related genes, and segregation data was not provided (Hooper et al., 2014; Wojcik et al., 2018); Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 92 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); This variant is associated with the following publications: (PMID: 29954705, 31980526, 32041611, 24591733, 28951076, 34662886)
AiLife Diagnostics, AiLife Diagnostics	RCV001570903	SCV002502657	likely pathogenic	not provided	2021-08-09	criteria provided, single submitter	clinical testing
Mendelics	RCV002246434	SCV002518480	pathogenic	Familial type 5 hyperlipoproteinemia	2022-05-04	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002424992	SCV002680958	likely pathogenic	Cardiovascular phenotype	2022-03-30	criteria provided, single submitter	clinical testing	The c.823C>T (p.Q275*) alteration, located in exon 4 (coding exon 3) of the APOA5 gene, consists of a C to T substitution at nucleotide position 823. This changes the amino acid from a glutamine (Q) to a stop codon at amino acid position 275. While premature stop codons are typically deleterious in nature, this stop codon occurs at the 3' terminus of APOA5 and is not expected to trigger nonsense-mediated mRNA decay. However, this variant results in the loss of >25% of the protein, including the C-terminal domain which has been implicated in lipid binding, and is expected to result in loss of function by premature protein truncation. Based on data from gnomAD, the T allele has an overall frequency of <0.01% (10/246736) total alleles studied. The highest observed frequency was 0.01% (8/113066) of European (non-Finnish) alleles. This variant has been detected in conjunction with another APOA5 nonsense alteration (phase unclear) in a patient with severe hypertriglyceridemia and acute pancreatitis (Hooper, 2014). This variant has also been seen with a nonsense alteration in CREB3L3 in a patient with hypertriglyceridemia exacerbated by estrogen administration who also had a high polygenic risk score for elevated triglycerides (W&oacute;jcik, 2018). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002501921	SCV002809848	likely pathogenic	Familial type 5 hyperlipoproteinemia; Hypertriglyceridemia 1	2021-11-02	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV002246434	SCV003835536	pathogenic	Familial type 5 hyperlipoproteinemia	2022-11-10	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003147637	SCV003836046	pathogenic	Hypertriglyceridemia 1	2022-11-10	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001570903	SCV004294943	uncertain significance	not provided	2023-12-30	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln275*) in the APOA5 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 92 amino acid(s) of the APOA5 protein. This variant is present in population databases (rs149808404, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with autosomal recessive hypertriglyceridaemia (PMID: 24591733, 32041611, 36325899). ClinVar contains an entry for this variant (Variation ID: 1204530). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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.