Submissions for variant NM_000384.3(APOB):c.13028_13029del (p.Tyr4343fs)

dbSNP: rs760832994

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Revvity Omics, Revvity	RCV001785651	SCV002021416	likely pathogenic	not provided	2022-12-13	criteria provided, single submitter	clinical testing
GeneDx	RCV001785651	SCV002526180	likely pathogenic	not provided	2023-07-25	criteria provided, single submitter	clinical testing	Observed in an individual with familial hypercholesterolemia (Al-Khateeb et al., 2013); however, patient-specific details were not provided and some individuals from this cohort harbored additional variants in the LDLR gene; Not observed at significant frequency in large population cohorts (gnomAD); Frameshift variant predicted to result in protein truncation, as the last 221 amino acids are replaced with 2 different amino acids, and other loss-of-function variants have been reported downstream in HGMD.; This variant is associated with the following publications: (PMID: 23775634, 36499307, 32009526)
Ambry Genetics	RCV002383985	SCV002692494	uncertain significance	Cardiovascular phenotype	2023-03-20	criteria provided, single submitter	clinical testing	The c.13028_13029delAT variant, located in coding exon 29 of the APOB gene, results from a deletion of two nucleotides at nucleotide positions 13028 to 13029, causing a translational frameshift with a predicted alternate stop codon (p.Y4343Cfs*3). This alteration occurs at the 3' terminus of the APOB gene, is not expected to trigger nonsense-mediated mRNAdecay, and only impacts the last 221 amino acids (4.8%) of the protein. This alteration has been reported in individuals from hyperlipidemia cohorts; however, clinical details were limited and cases may overlap (Al-Khateeb AR et al. Biochem. Genet., 2013 Oct;51:811-23; Razman AZ et al. Int J Mol Sci. 2022 Nov;23(23)). The C-terminus has been indicated to play a role in both lipoprotein assembly and LDLR binding (McCormick SP et al. J. Biol. Chem., 1997 Sep;272:23616-22; Boren J et al. J. Clin. Invest., 1998 Mar;101:1084-93; Borén J et al. J. Biol. Chem., 2001 Mar;276:9214-8). However, the exact functional effect of this alteration is unknown. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
New York Genome Center	RCV002467842	SCV002764567	uncertain significance	Hypercholesterolemia, autosomal dominant, type B; Familial hypobetalipoproteinemia 1	2021-01-25	criteria provided, single submitter	clinical testing	The c.13028_13029del, p.Tyr4343CysfsTer3 variant identified in the APOB gene has been reported in an individual affected with a mild hypercholesterolemia [PMID:23775634]. This variant causing a frameshift at codon 4343 and a premature translational stop signal three amino acids downstream and the mutant mRNA may escape nonsense-mediated decay and may be expressed as a truncated protein that lacks the last 238 amino acids from the C-terminal end. This variant is found with low frequency in gnomAD v3.1 (1 heterozygotes, 0 homozygotes; allele frequency: 0.0006%) suggesting it is not a common benign variant in the populations represented in that database. Based on available evidence the c.13028_13029del, p.Tyr4343CysfsTer3 variant identified in the APOB gene is reported as a Variant of uncertain significance.
Invitae	RCV002467842	SCV003305305	uncertain significance	Hypercholesterolemia, autosomal dominant, type B; Familial hypobetalipoproteinemia 1	2022-07-21	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr4343Cysfs*3) in the APOB gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 221 amino acid(s) of the APOB protein. This variant is present in population databases (rs760832994, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with familial hypercholesterolemia (PMID: 23775634). ClinVar contains an entry for this variant (Variation ID: 440513). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003479145	SCV004222742	uncertain significance	not specified	2023-11-16	criteria provided, single submitter	clinical testing	Variant summary: APOB c.13028_13029delAT (p.Tyr4343CysfsX3) results in a premature termination codon, predicted to cause a truncation of the encoded protein, however, nonsense mediated decay is not expected. The variant allele was found at a frequency of 1.2e-05 in 242432 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.13028_13029delAT has been reported in the literature in individuals affected with Familial Hypercholesterolemia (Al-Khateeb_2013, Martin_2022). These reports do not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as VUS (n=3) and likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001785651	SCV004562377	uncertain significance	not provided	2023-11-14	criteria provided, single submitter	clinical testing	The APOB c.13028_13029del; p.Tyr4343CysfsTer3 variant (rs760832994) is reported in the literature in individuals from hyperlipidemia cohorts, however patient-specific details are limited and in one cohort some individuals also carried additional variants in the LDLR gene (Al-Khateeb 2013, Pottinger 2020, Razman 2022). The c.13028_13029del variant is reported in ClinVar (Variation ID: 440513). It is observed in the general population with an overall allele frequency of 0.0015% (4/273834 alleles) in the Genome Aggregation Database (v2.1.1). This variant results in a premature termination codon in the last exon of the APOB gene. While this may not lead to nonsense-mediated decay, it is expected to create a truncated APOB protein removing just under 5% of the protein. Due to limited information, the clinical significance of this variant is uncertain at this time. References: Al-Khateeb AR et al. Molecular description of familial defective APOB-100 in Malaysia. Biochem Genet. 2013 Oct;51(9-10):811-23. PMID: 23775634. Pottinger TD et al. Pathogenic and Uncertain Genetic Variants Have Clinical Cardiac Correlates in Diverse Biobank Participants. J Am Heart Assoc. 2020 Feb 4;9(3):e013808. PMID: 32009526. Razman AZ et al. Genetic Spectrum of Familial Hypercholesterolaemia in the Malaysian Community: Identification of Pathogenic Gene Variants Using Targeted Next-Generation Sequencing. Int J Mol Sci. 2022 Nov 29;23(23):14971. PMID: 36499307.
PreventionGenetics, part of Exact Sciences	RCV003935334	SCV004758782	likely pathogenic	APOB-related condition	2024-01-30	criteria provided, single submitter	clinical testing	The APOB c.13028_13029delAT variant is predicted to result in a frameshift and premature protein termination (p.Tyr4343Cysfs*3). This variant has been reported in individuals with familial hypercholesterolemia (Al-Khateeb et al. 2013. PubMed ID: 23775634; Razman et al. 2022. PubMed ID: 36499307). This variant is reported in 0.015% of alleles in individuals of East Asian descent in gnomAD. In ClinVar, this variant has conflicting interpretations of uncertain significance and likely pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/440513/). Frameshift variants in APOB are expected to be pathogenic. This variant is interpreted as likely pathogenic.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000508887	SCV000605950	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research