Submissions for variant NM_000384.3(APOB):c.10238del (p.Thr3413fs)

gnomAD frequency: 0.00003  dbSNP: rs756209187

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000501647	SCV000593264	pathogenic	Hypobetalipoproteinemia	2016-04-29	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001837939	SCV001208232	pathogenic	Hypercholesterolemia, autosomal dominant, type B; Familial hypobetalipoproteinemia 1	2024-07-22	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Thr3413Metfs*2) in the APOB gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in APOB are known to be pathogenic (PMID: 20032471). This variant is present in population databases (rs756209187, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with autosomal dominant hypobetalipoproteinemia (PMID: 1431583). This variant is also known as c.10366del. ClinVar contains an entry for this variant (Variation ID: 434252). For these reasons, this variant has been classified as Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001248960	SCV001422759	likely pathogenic	Familial hypobetalipoproteinemia 1	2020-01-22	criteria provided, single submitter	curation	The p.Thr3413Metfs variant in APOB has not been previously reported in individuals with low LDL but has been identified in in 0.00155% (2/129014) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs756209187). This variant has also been reported in ClinVar (VariationID: 434252) as pathogenic by the University of Chicago. This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 3413 and leads to a premature termination codon 2 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the APOB gene is an established disease mechanism in autosomal recessive low LDL. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PVS1 (Richards 2015).
Revvity Omics, Revvity	RCV001783000	SCV002018294	pathogenic	not provided	2022-11-21	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV001837939	SCV002810491	pathogenic	Hypercholesterolemia, autosomal dominant, type B; Familial hypobetalipoproteinemia 1	2021-10-17	criteria provided, single submitter	clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV000501647	SCV004046197	pathogenic	Hypobetalipoproteinemia		criteria provided, single submitter	clinical testing	This variant is also referred to as c.10366del in the literature. This frameshifting variant in exon 26 of 29 introduces a premature stop codon and is therefore predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported as a heterozygous change in patients with Hypobetalipoproteinemia (PMID: 1431583). Loss-of-function variation in APOB is an established mechanism of disease (PMID: 30939045). Experimental studies have shown that this c.10238del (p.Thr3413MetfsTer2) change results in decreased LDL-cholesterol levels and reduced APOB protein concentrations (PMID: 1431583). The c.10238del (p.Thr3413MetfsTer2) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.0007% (2/282662) and thus is presumed to be rare. Based on the available evidence, the c.10238del (p.Thr3413MetfsTer2) variant is classified as Pathogenic.
Ambry Genetics	RCV004023361	SCV005034952	pathogenic	Cardiovascular phenotype	2023-10-25	criteria provided, single submitter	clinical testing	The c.10238delC pathogenic mutation, located in coding exon 26 of the APOB gene, results from a deletion of one nucleotide at nucleotide position 10238, causing a translational frameshift with a predicted alternate stop codon (p.T3413Mfs*2). This variant has been detected in the heterozygous state in individuals with low LDL cholesterol, some of whom also had fatty liver disease (Krul ES et al. J Lipid Res. 1992 Jul;33(7):1037-50; Vilar-Gomez E et al. J Clin Lipidol. 2021 Dec;15(2):275-291). One study reported this variant to result in increased LDL receptor binding (Krul ES et al. J Lipid Res. 1992 Jul;33(7):1037-50). Although biallelic loss of function alterations in APOB have been associated with autosomal recessive hypobetalipoproteinemia, haploinsufficiency for APOB has not been clearly established as a mechanism of disease for autosomal dominant familial hypercholesterolemia. Based on the supporting evidence, this variant would be expected to cause autosomal recessive hypobetalipoproteinemia when present along with a second pathogenic or likely pathogenic variant on the other allele; however, the association of this alteration with autosomal dominant familial hypercholesterolemia is unlikely.
New York Genome Center	RCV004554792	SCV005044151	likely pathogenic	Hypercholesterolemia, autosomal dominant, type B	2022-10-14	criteria provided, single submitter	clinical testing	The heterozygous c.10238del variant in APOB has previously been reported in individuals with associated familial hypercholesterolemia [PMID: 32719484] and it has been deposited in ClinVar (Var ID: 434252) as Pathogenic/Likely pathogenic. The c.10238del variant is observed in 7 alleles (~0.0011% minor allele frequency with 0 homozygotes) in population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8), suggesting it is not a common benign variant in the populations represented in those databases. The c.10238del variant in APOB is located in exon 26 of this 29-exon gene, predicted to incorporate a premature termination codon (p.(Thr3413MetfsTer2)), and is expected to result in loss-of-function via nonsense mediated decay. Multiple loss-of-function variants that are downstream to the c.10238del variant have been reported in ClinVar or literature in affected individuals. Based on available evidence this inherited c.10238del, p.(Thr3413MetfsTer2) variant identified in APOB is classified as Likely Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV004737572	SCV005362425	pathogenic	APOB-related disorder	2024-05-17	no assertion criteria provided	clinical testing	The APOB c.10238delC variant is predicted to result in a frameshift and premature protein termination (p.Thr3413Metfs*2). This variant has been reported to segregate with disease in a three-generation family with hypobetalipoproteinemia (Krul et al. 1992. PubMed ID: 1431583). It has also been reported in individuals with nonalcoholic fatty liver disease (Vilar-Gomez et al. 2021. PubMed ID: 33454241). This variant is reported in 0.0016% of alleles in individuals of European (non-Finnish) descent in gnomAD. Frameshift variants in APOB are expected to be pathogenic and this variant has been interpreted as pathogenic and likely pathogenic by other laboratories in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/434252/). This variant is interpreted as pathogenic.