Submissions for variant NM_000384.3(APOB):c.1010T>A (p.Ile337Asn) (rs148126873)

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Total submissions: 2

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000706833	SCV000835906	uncertain significance	Familial hypercholesterolemia 2; Hypobetalipoproteinemia, familial, 1	2018-07-03	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine with asparagine at codon 337 of the APOB protein (p.Ile337Asn). The isoleucine residue is weakly conserved and there is a large physicochemical difference between isoleucine and asparagine. This variant is present in population databases (rs148126873, ExAC 0.03%). This variant has not been reported in the literature in individuals with APOB-related disease. 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: "Benign"; Align-GVGD: "Class C0"). 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.
Color	RCV000775588	SCV000909952	uncertain significance	Familial hypercholesterolemia	2018-09-24	criteria provided, single submitter	clinical testing	Variant of Uncertain Significance due to insufficient evidence: This missense variant (also known as p.Ile319Asn in the mature protein) is located in the beta alpha 1 domain of the APOB protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has the variant been reported in individuals affected with familial hypercholesterolemia in the literature. This variant has been identified in 5/121412 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.

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