ClinVar Miner

Submissions for variant NM_000384.3(APOB):c.10708C>T (p.His3570Tyr) (rs201736972)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000766982 SCV000589625 uncertain significance not provided 2018-07-19 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the APOB gene. The H3570Y variant has been previously reported in association with familial hypercholesterolemia and coronary heart disease (Soufi et al., 2004; Liyanage et al., 2008; Galaska et al., 2016). The H3570Y variant is observed in 18/66660 (0.03%) alleles from individuals of European background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The H3570Y variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is not conserved, and in silico analysis predicts this variant likely does not alter the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000498755 SCV000711795 uncertain significance not specified 2019-04-18 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The p.His3570Tyr variant (also reported as p.His3543Tyr) in APOB has been reported in 7 individuals with hypercholesterolemia, one individual with suspected hypercholesterolemia, one individual with sudden cardiac death and segregated with disease in 3 affected relatives from 2 families, but was not detected in one affected family member (Soufi 2004, Basistova 2007, Liyanage 2008, Galaska 2016, Mullertz 2018). This variant has also been identified in 0.027% (35/128752) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org) and is reported in ClinVar (Variation ID: 431988). This frequency is low enough to be consistent with the frequency of familial hypercholesterolemia in the general population. Histidine (His) at position 3570 is not conserved in mammals or evolutionarily distant species, and 3 mammals (squirrel, ferret, and Chinese hamster) and 18 other species carry a Tyrosine (Tyr), raising the possibility that this change may be tolerated. Additional computational prediction tools analysis suggest that the p.His3570Tyr variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.His3570Tyr variant is uncertain due to conflicting data. ACMG/AMP Criteria applied: PS4_Moderate, BP4_Strong, BS4.
Color RCV000775453 SCV000909816 uncertain significance Familial hypercholesterolemia 2019-06-05 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000766982 SCV001152121 uncertain significance not provided 2018-10-01 criteria provided, single submitter clinical testing
Invitae RCV001067746 SCV001232820 uncertain significance Familial hypercholesterolemia 2; Hypobetalipoproteinemia, familial, 1 2019-12-28 criteria provided, single submitter clinical testing This sequence change replaces histidine with tyrosine at codon 3570 of the APOB protein (p.His3570Tyr). The histidine residue is weakly conserved and there is a moderate physicochemical difference between histidine and tyrosine. This variant is present in population databases (rs201736972, ExAC 0.03%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been observed in individuals affected with familial hypercholesterolemia (PMID: 18325181, 17046772) or coronary heart disease (PMID: 15135245). This variant is also known as p.His3543Tyr in the literature. ClinVar contains an entry for this variant (Variation ID: 431988). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The tyrosine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000508757 SCV000605960 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research

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