Submissions for variant NM_000527.5(LDLR):c.1706-10G>A

Total submissions: 30

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000211645	SCV002506376	likely benign	Hypercholesterolemia, familial, 1	2022-03-16	reviewed by expert panel	curation	The NM_000527.5(LDLR):c.1706-10G>A variant is classified as Likely benign for Familial Hypercholesterolemia by applying evidence codes BS1, BS3_supporting and PP1_moderate 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: BS1 - FAF = 0.002911 (0.2911%) in Latino/Admixed American exomes (gnomAD v2.1.1), so BS1 is Met. BS3_supporting - 2 Level 3 assays: PMID: 25741862: Heterozygous patients' lymphocytes, RNA assays - result - Normal LDLR transcripts identified by sequencing. PMID: 19208450: Heterozygous patients' Epstein Barr virus transformed lymphocytes, RNA assays - result - Normal LDLR transcripts, 43% of mutant transcripts (from total transcripts) in htz cells. ---- Aberrant transcripts are not detected, so BS3_Supporting is Met. PP1_moderate - Variant segregates with FH phenotype in at least 5 informative meiosis from 2 families from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge: 5 affected family members have the variant, so PP1_Moderate is Met. Variant has 1 Strong plus 1 Supporting evidence codes towards Benign, enough to classify as Likely benign and only 1 Moderate evidence code towards Pathogenic, not enough for Likely pathogenic, so we are confident in classifying this variant as Likely benign.
LDLR-LOVD, British Heart Foundation	RCV000211645	SCV000295599	likely benign	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	RCV000211645	SCV000322971	likely benign	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research	1/125 non-FH individuals
Cardiovascular Biomarker Research Laboratory, Mayo Clinic	RCV000211645	SCV000323103	uncertain significance	Hypercholesterolemia, familial, 1	2016-08-31	criteria provided, single submitter	research	MAF =<0.3%, LDL-C >=160 mg/dL
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	RCV000211645	SCV000503394	benign	Hypercholesterolemia, familial, 1	2016-12-16	criteria provided, single submitter	clinical testing	subjects mutated among 2600 FH index cases screened = 15
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000455738	SCV000539506	likely benign	not specified	2017-02-03	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This is an intronic variant in LDLR. It is classified as DM? in HGMD. It has been reported in 2 probands with hypercholesterolemia but in both co-occurred with another variant. It is classified in ClinVar with 1 star as Benign by Cardiovascular Genetics Laboratory,PathWest Laboratory Medicine WA - Fiona Stanley Hospital, Likely benign by British Heart Foundation and Instituto Nacional de Saude Doutor Ricardo Jorge (in 1/125 non-FH individuals), and as VUS by CHOP. It has a max MAF in ExAC of 0.38% (44 Latino alleles) and in gnomAD of 0.4% (41 Ashkenazi and 122 Latino alleles).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000771093	SCV000556772	benign	Familial hypercholesterolemia	2024-01-31	criteria provided, single submitter	clinical testing
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000211645	SCV000583867	likely benign	Hypercholesterolemia, familial, 1	2017-03-30	criteria provided, single submitter	clinical testing
Laboratory of Genetics and Molecular Cardiology, University of São Paulo	RCV000211645	SCV000588603	likely benign	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Fundacion Hipercolesterolemia Familiar	RCV000211645	SCV000607628	likely benign	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Color Diagnostics, LLC DBA Color Health	RCV000771093	SCV000689765	benign	Familial hypercholesterolemia	2022-01-19	criteria provided, single submitter	clinical testing
GeneDx	RCV000455738	SCV000730511	benign	not specified	2017-12-04	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Iberoamerican FH Network	RCV000211645	SCV000748152	likely benign	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Robarts Research Institute, Western University	RCV000211645	SCV000782923	likely benign	Hypercholesterolemia, familial, 1	2018-01-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759075	SCV000888162	benign	not provided	2022-05-26	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000771093	SCV000902688	benign	Familial hypercholesterolemia	2018-06-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000211645	SCV001281863	uncertain significance	Hypercholesterolemia, familial, 1	2018-08-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
CeGaT Center for Human Genetics Tuebingen	RCV000759075	SCV001747208	likely benign	not provided	2022-06-01	criteria provided, single submitter	clinical testing	LDLR: BP4, BS1
Ambry Genetics	RCV002399781	SCV002712874	benign	Cardiovascular phenotype	2021-09-28	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Fulgent Genetics, Fulgent Genetics	RCV000211645	SCV002804653	likely benign	Hypercholesterolemia, familial, 1	2022-04-28	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000759075	SCV004564798	benign	not provided	2023-11-08	criteria provided, single submitter	clinical testing
GENinCode PLC	RCV000771093	SCV005073993	benign	Familial hypercholesterolemia	2022-07-15	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV000759075	SCV005312108	benign	not provided		criteria provided, single submitter	not provided
Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	RCV000211645	SCV000268631	benign	Hypercholesterolemia, familial, 1	2015-04-02	no assertion criteria provided	clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000211645	SCV000296925	uncertain significance	Hypercholesterolemia, familial, 1	2015-09-02	flagged submission	clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000211645	SCV000606493	benign	Hypercholesterolemia, familial, 1		no assertion criteria provided	research
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000211645	SCV000733826	likely benign	Hypercholesterolemia, familial, 1		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000455738	SCV001922575	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000759075	SCV001975804	likely benign	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000771093	SCV002086435	likely benign	Familial hypercholesterolemia	2019-11-06	no assertion criteria provided	clinical testing