Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Institute for Integrative and Experimental Genomics, |
RCV000172960 | SCV000212135 | likely pathogenic | Hypercholesterolemia, familial, 1 | criteria provided, single submitter | research | ||
| Color Diagnostics, |
RCV001190239 | SCV001357686 | likely benign | Familial hypercholesterolemia | 2018-05-08 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003398872 | SCV004121996 | uncertain significance | not specified | 2023-10-23 | criteria provided, single submitter | clinical testing | Variant summary: LDLR c.811G>A (p.Val271Ile) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251456 control chromosomes. c.811G>A at a heterozygous state has been reported in the literature in several individuals affected with Hypercholesterolemia, or Coronary Aartery Disease and Myocardial Infarction with elevated low-density lipoprotein cholesterollevels (examples, Branne_2016, Huang_2020, Tomar_2022, Martin-Campos_2018). Particularly, Branne_2016 reported this variant in three siblings, two of whom were diagnosed with Coronary Aartery Disease and Myocardial Infarction, and the rest carrier remained unaffected with elevated LDLC levels. However, other studies evaluated this variant insignificant or Likely benign. These report(s) do not provide unequivocal conclusions about association of the variant with autosomal dominant or autosomal recessive Hypercholesterolemia. 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: 26036859, 33994402, 30293936, 35130036). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. |
| Invitae | RCV001190239 | SCV004453101 | likely pathogenic | Familial hypercholesterolemia | 2023-11-17 | criteria provided, single submitter | clinical testing | This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 271 of the LDLR protein (p.Val271Ile). This variant is present in population databases (rs749220643, gnomAD 0.01%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 26036859, 29233637, 30293936, 33994402; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 189297). 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 not expected to disrupt LDLR protein function with a negative predictive value of 95%. 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. |