ClinVar Genomic variation as it relates to human health

subject mutated among 2600 FH index cases screened = 1 /FH-UK/software prediction damaging

Variant summary: LDLR c.1946C>T (p.Pro649Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251472 control chromosomes (gnomAD). c.1946C>T has been reported in the literature in individuals affected with Familial Hypercholesterolemia (e.g. Day_1997, Tosi_2007, Du_2022, Sustar_2022). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 9259195, 36325061, 35913489, 17094996). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as either VUS or likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 9259195). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 649 of the LDLR protein (p.Pro649Leu). This variant is not present in population databases (gnomAD no frequency). This variant is also known as P628L. ClinVar contains an entry for this variant (Variation ID: 252122). 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 LDLR protein function. This variant disrupts the p.Pro649 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20809525; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

This missense variant replaces proline with leucine at codon 649 of the LDLR protein. This variant is also known as p.Pro628Leu in the mature protein. This variant alters a conserved AA1 residue in the LDLR type B repeat 6 of the LDLR protein (a.a. 616-658), where pathogenic missense variants are found enriched (ClinVar-LDLR). Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in four individuals affected with familial hypercholesterolemia (PMID: 9259195, 17094996, 18325082, 35913489, 36325061; ClinVar SCV000503435.1). This variant has not been identified 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.

The p.P649L variant (also known as c.1946C>T), located in coding exon 13 of the LDLR gene, results from a C to T substitution at nucleotide position 1946. The proline at codon 649 is replaced by leucine, an amino acid with similar properties. This alteration has been reported in familial hypercholesterolemia (FH) cohorts (Day IN et al. Hum Mutat, 1997;10:116-27; Tosi I et al. Atherosclerosis, 2007 Sep;194:102-11). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

LDLR: PM1, PM2, PS4:Moderate, PP4