ClinVar Genomic variation as it relates to human health

This sequence change replaces methionine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 412 of the LDLR protein (p.Met412Leu). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with LDLR-related conditions. ClinVar contains an entry for this variant (Variation ID: 918996). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant disrupts the p.Met412 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11194027, 16406299, 20599862). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.

This missense variant replaces methionine with leucine at codon 412 of the LDLR protein. This variant is also known as p.Met391Leu 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with LDLR-related disorders in the literature. This variant has been identified in 1/251176 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.

This missense variant replaces methionine with leucine at codon 412 of the LDLR protein. This variant is also known as p.Met391Leu 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with LDLR-related disorders in the literature. This variant has been identified in 1/251176 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.