ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.2291T>C (p.Ile764Thr)

gnomAD frequency: 0.00001  dbSNP: rs759440817
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000238374 SCV000295932 likely benign Hypercholesterolemia, familial, 1 2016-03-25 criteria provided, single submitter literature only
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge RCV000238374 SCV000323006 benign Hypercholesterolemia, familial, 1 2016-03-01 criteria provided, single submitter research 0/200 non-FH alleles
Color Diagnostics, LLC DBA Color Health RCV001192333 SCV001360365 uncertain significance Familial hypercholesterolemia 2023-10-12 criteria provided, single submitter clinical testing This missense variant replaces isoleucine with threonine at codon 764 in the O-linked oligo-saccharide domain of the LDLR protein. This variant is also known as p.Ile743Thr in the mature protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study showed that this variant had no impact on LDLR cell surface expression or activity (PMID: 34167030). This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 26020417, 29353225, 34167030; ClinVar: SCV003280202.1). This variant has been identified in 10/251168 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Labcorp Genetics (formerly Invitae), Labcorp RCV001192333 SCV003280202 uncertain significance Familial hypercholesterolemia 2022-05-06 criteria provided, single submitter clinical testing This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 764 of the LDLR protein (p.Ile764Thr). This variant is present in population databases (rs759440817, gnomAD 0.03%). This missense change has been observed in individuals with clinical features of familial hypercholesterolemia (PMID: 26020417, 29353225; Invitae). ClinVar contains an entry for this variant (Variation ID: 252265). 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 threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
All of Us Research Program, National Institutes of Health RCV000238374 SCV004818521 uncertain significance Hypercholesterolemia, familial, 1 2023-11-02 criteria provided, single submitter clinical testing This missense variant replaces isoleucine with threonine at codon 764 in the O-linked oligo-saccharide domain of the LDLR protein. This variant is also known as p.Ile743Thr in the mature protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study showed that this variant had no impact on LDLR cell surface expression or activity (PMID: 34167030). This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 26020417, 29353225, 34167030; ClinVar: SCV003280202.1). This variant has been identified in 10/251168 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

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