Submissions for variant NM_000527.5(LDLR):c.251C>T (p.Pro84Leu)

dbSNP: rs875989892

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000211630	SCV004022411	uncertain significance	Hypercholesterolemia, familial, 1	2023-03-20	reviewed by expert panel	curation	The NM_000527.5(LDLR):c.251C>T (p.Pro84Leu) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence code PM2, PP1_Moderate and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 - This variant is absent from gnomAD (gnomAD v2.1.1) PP1_Moderate - Variant segregates with FH phenotype in at least 4 informative meiosis from 2 families from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA). In one family 2 family members positive for variant with LDL > 75th percentile, in the other 2 family members negative for variantwith LDL < 50th percentile. PP4 - Variant meets PM2 and is identified in one index case who fulfill FH/DLCN>=6 criteria for FH from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA) after alternative causes of high cholesterol were excluded.
LDLR-LOVD, British Heart Foundation	RCV000211630	SCV000294556	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Labcorp Genetics (formerly Invitae), Labcorp	RCV003581585	SCV004298309	pathogenic	Familial hypercholesterolemia	2024-01-11	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 84 of the LDLR protein (p.Pro84Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant hypercholesterolemia (PMID: 22883975, 33740630). ClinVar contains an entry for this variant (Variation ID: 226310). 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 with a positive predictive value of 95%. This variant disrupts the p.Pro84 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16159606, 33740630). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
All of Us Research Program, National Institutes of Health	RCV000211630	SCV004832796	uncertain significance	Hypercholesterolemia, familial, 1	2023-06-26	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Pro63Leu in the mature protein) replaces proline with leucine at codon 84 of the LDLR protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 22883975, 33740630). 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.
Ambry Genetics	RCV005365145	SCV006019624	uncertain significance	Cardiovascular phenotype	2025-01-10	criteria provided, single submitter	clinical testing	The p.P84L variant (also known as c.251C>T), located in coding exon 3 of the LDLR gene, results from a C to T substitution at nucleotide position 251. The proline at codon 84 is replaced by leucine, an amino acid with similar properties. This variant was reported in individual(s) with features consistent with familial hypercholesterolemia (FH) (Hooper AJ et al. Atherosclerosis, 2012 Oct;224:430-4; Leren TP et al. Atherosclerosis, 2021 Apr;322:61-66). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV003581585	SCV006063533	uncertain significance	Familial hypercholesterolemia	2023-03-27	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Pro63Leu in the mature protein) replaces proline with leucine at codon 84 of the LDLR protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 22883975, 33740630). 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.
Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	RCV000211630	SCV000268545	pathogenic	Hypercholesterolemia, familial, 1	2011-10-07	no assertion criteria provided	clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000211630	SCV000606049	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research