Submissions for variant NM_000384.3(APOB):c.12460G>T (p.Glu4154Ter)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV005220787	SCV005861976	uncertain significance	Hypercholesterolemia, autosomal dominant, type B; Familial hypobetalipoproteinemia 1	2024-03-20	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu4154*) in the APOB gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 410 amino acid(s) of the APOB protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with APOB-related conditions. This variant disrupts a region of the APOB protein in which other variant(s) (p.Tyr4380*) have been observed in individuals with APOB-related conditions (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. 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.
PreventionGenetics, part of Exact Sciences	RCV004534612	SCV004715967	likely pathogenic	APOB-related disorder	2023-12-21	no assertion criteria provided	clinical testing	The APOB c.12460G>T variant is predicted to result in premature protein termination (p.Glu4154*). To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD. Nonsense variants in APOB are expected to be pathogenic. This variant is interpreted as likely pathogenic.