Submissions for variant NM_000527.5(LDLR):c.1765G>C (p.Asp589His)

dbSNP: rs201971888

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV002505198	SCV002817144	uncertain significance	Hypercholesterolemia, familial, 1	2022-08-29	reviewed by expert panel	curation	The NM_000527.5(LDLR):c.1765G>C (p.Asp589His) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2 and BP4 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 - PopMax MAF = 0.000008790 (0.0009%) in Non-Finnish European exomes+genomes (gnomAD v2.1.1) BP4 - REVEL = 0.424. It is below 0.5, splicing evaluation needed. Functional data on splicing not available. A) variant not on limits. B) does not create AG or GT Variant is not predicted to alter splicing
Color Diagnostics, LLC DBA Color Health	RCV001804889	SCV002052040	uncertain significance	Familial hypercholesterolemia	2021-07-27	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Asp568His in the mature protein) replaces aspartic acid with histidine at codon 589 of the LDLR protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). One high-throughput study suggested this variant has normal function (PMID: 25647241). This variant has been reported in one individual who survived acute myocardial infarction (PMID: 25647241). This variant has been identified in 1/251490 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.
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV002505198	SCV004807976	uncertain significance	Hypercholesterolemia, familial, 1	2024-03-29	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001804889	SCV005836828	uncertain significance	Familial hypercholesterolemia	2024-12-23	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 589 of the LDLR protein (p.Asp589His). This variant is present in population databases (rs201971888, 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: 183125). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt LDLR protein function with a positive predictive value of 95%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on LDLR function (PMID: 25647241). 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.
Dept. of Genetics and Pharmacogenomics, Merck Research Labs	RCV000162000	SCV000189575	not provided	not provided		no assertion provided	in vitro