Submissions for variant NM_000384.3(APOB):c.13153C>T (p.Arg4385Cys)

dbSNP: rs864309556

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000202903	SCV000257675	uncertain significance	Hypercholesterolemia, familial, 1	2015-06-26	criteria provided, single submitter	clinical testing
Invitae	RCV001853264	SCV002205210	uncertain significance	Hypercholesterolemia, autosomal dominant, type B; Familial hypobetalipoproteinemia 1	2022-06-13	criteria provided, single submitter	clinical testing	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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 218441). This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 22294733). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 4385 of the APOB protein (p.Arg4385Cys).
New York Genome Center	RCV001853264	SCV004176207	uncertain significance	Hypercholesterolemia, autosomal dominant, type B; Familial hypobetalipoproteinemia 1	2023-07-13	criteria provided, single submitter	clinical testing	The c.13153C>T p.(Arg4385Cys) missense variant identified in the APOB gene has been reported in an individual with familial hypercholesterolemia [PMID:22294733]. This variant has been deposited in ClinVar as a variant of uncertain significance [ClinVar ID: 218441]. It is observed in 2 alleles in population databases (~0.0006 %MAF with 0 homozygote in gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8), suggesting that it is not a common benign variant in the populations represented in those databases. This c.13153C>T in APOB gene is located in exon 29 if this 29-exon gene, replacing arginine with cysteine at codon 4385 of the APOB protein [p.(Arg4385Cys)]. In silico predictions are inconclusive of the variant’s effect (REVEL=0.199); however, there are no functional studies to support or refute these predictions. In summary, due to the lack of compelling evidence for its pathogenicity, the c.13153C>T p.(Arg4385Cys) missense variant identified in the APOB gene is reported as a Variant of Uncertain Significance.
Clinical Genetics, Academic Medical Center	RCV001729455	SCV001978894	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001729455	SCV001979931	uncertain significance	not provided		no assertion criteria provided	clinical testing