Submissions for variant NM_000527.5(LDLR):c.2242G>A (p.Asp748Asn)

dbSNP: rs150104358

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000237615	SCV000295925	likely benign	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Illumina Laboratory Services, Illumina	RCV000237615	SCV000410544	uncertain significance	Hypercholesterolemia, familial, 1	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Robarts Research Institute, Western University	RCV000237615	SCV000484755	uncertain significance	Hypercholesterolemia, familial, 1	2019-08-22	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001178125	SCV001342485	likely benign	Familial hypercholesterolemia	2021-03-02	criteria provided, single submitter	clinical testing
Invitae	RCV001178125	SCV001531711	likely benign	Familial hypercholesterolemia	2024-01-15	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000237615	SCV003816522	uncertain significance	Hypercholesterolemia, familial, 1	2022-03-31	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000162012	SCV004219974	uncertain significance	not provided	2023-05-23	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals with suspected to severe hypercholesterolemia (PMIDs: 27765764 (2016), 27044878 (2017), 32044282 (2020)) and individuals with early-onset myocardial infarction (PMIDs: 25647241 (2015) and 25487149 (2015)). An in vitro functional study indicated an inconclusive effect of this variant on LDLR function (PMID: 25647241 (2015)). The frequency of this variant in the general population, 0.00052 (16/30616 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Dept. of Genetics and Pharmacogenomics, Merck Research Labs	RCV000162012	SCV000189588	not provided	not provided		no assertion provided	in vitro
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000237615	SCV000606618	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research
Natera, Inc.	RCV001178125	SCV002086870	uncertain significance	Familial hypercholesterolemia	2020-02-25	no assertion criteria provided	clinical testing