ClinVar Miner

Submissions for variant NM_000384.3(APOB):c.10182G>T (p.Lys3394Asn)

dbSNP: rs1382988295
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge RCV000505259 SCV000599289 likely pathogenic Hypercholesterolemia, familial, 1 2016-03-01 criteria provided, single submitter curation
Labcorp Genetics (formerly Invitae), Labcorp RCV001837941 SCV001207572 pathogenic Hypercholesterolemia, autosomal dominant, type B; Familial hypobetalipoproteinemia 1 2020-01-06 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt APOB protein function. This variant has been observed to segregate with familial hypercholesterolemia in a family (PMID: 22408029). ClinVar contains an entry for this variant (Variation ID: 438310). This variant is not present in population databases (ExAC no frequency). This sequence change replaces lysine with asparagine at codon 3394 of the APOB protein (p.Lys3394Asn). The lysine residue is moderately conserved and there is a moderate physicochemical difference between lysine and asparagine.
Fulgent Genetics, Fulgent Genetics RCV001837941 SCV002799773 likely pathogenic Hypercholesterolemia, autosomal dominant, type B; Familial hypobetalipoproteinemia 1 2021-07-07 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV005230986 SCV005878341 likely pathogenic not provided 2024-07-26 criteria provided, single submitter clinical testing The APOB c.10182G>T; p.Lys3394Asn variant (rs1382988295, ClinVar Variation ID: 438310), is reported in the literature in multiple individuals affected with familial hypercholesterolemia (Motazacker 2012, Reijman 2023, Sturm 2021). This variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.281). In vitro functional analyses found this variant attenuated binding to the LDLR significantly (Motazacker 2012). Based on available information, this variant is considered to be likely pathogenic. References: Motazacker MM et al. Advances in genetics show the need for extending screening strategies for autosomal dominant hypercholesterolaemia. Eur Heart J. 2012 Jun;33(11):1360-6. PMID: 22408029. Reijman MD et al. Genotype-phenotype correlation in a large cohort of pediatric patients with heterozygous and homozygous familial hypercholesterolemia. Curr Opin Lipidol. 2023 Dec 1;34(6):287-295. PMID: 36752612. Sturm AC et al. Limited-Variant Screening vs Comprehensive Genetic Testing for Familial Hypercholesterolemia Diagnosis. JAMA Cardiol. 2021 Aug 1;6(8):902-909. PMID: 34037665.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum RCV000505259 SCV000605969 pathogenic Hypercholesterolemia, familial, 1 no assertion criteria provided research

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