Submissions for variant NM_000527.5(LDLR):c.1920C>T (p.Asn640=)

gnomAD frequency: 0.00319  dbSNP: rs5926

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000231947	SCV004022398	benign	Hypercholesterolemia, familial, 1	2023-01-27	reviewed by expert panel	curation	The NM_000527.5 (LDLR):c.1920C>T (p.Asn640=) variant is classified as Benign for Familial Hypercholesterolemia by applying evidence codes (BA1, BP4, BP7, BS3_Supporting) 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: BA1: FAF=0.03838 in Ashkenazi Jewish population in gnomAD (gnomAD 2.1.1). BP4: No REVEL, splicing evaluation required. A) not in limit. B) does not create AG or GT. C) there is a GT nearby. Var cryptic score/Wt cryptic score=0.69, it is not above 1.1, and Var cryptic score/Wt score= -0.80, it is not above 0.9. Variant is not predicted to alter splicing. BP7: Variant is synonymous and meets BP4. BS3_Supporting: Level 3 assay with heterozygous patients’ lymphocytes, RNA assays shown normal LDLR transcripts, reported by Medeiros et al, 2016, from Instituto Nacional de Saude Doutor Ricardo Jorge, Lisbon, Portugal, PMID 26020417. Functional data is consistent with no damaging effect. PP4, PS4 not met: Variant did not meet PM2. PP1 not met: There are 2 relatives without the variant had LDL-C <50th percentile in 1 family, however the index case did not meet Simon Broome criteria for FH diagnosis, reported in VCI from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge. BS4 not met: There are 2 relatives without the variant had LDL-C >75th percentile in 1 family, however the index case did not meet Simon Broome criteria for FH diagnosis, and there is no instance where an unaffected family member carries the variant, reported in VCI from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge. BP2 not met: Variant identified in an index case with heterozygous FH phenotype and an unspecified LDLR variant with unknown pathogenicity and phase, reported in VCI from Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, Lyon, France.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000858146	SCV000285023	benign	Familial hypercholesterolemia	2024-01-31	criteria provided, single submitter	clinical testing
LDLR-LOVD, British Heart Foundation	RCV000231947	SCV000295754	benign	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	RCV000231947	SCV000322987	uncertain significance	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research	0/95 non-FH individuals
Cardiovascular Biomarker Research Laboratory, Mayo Clinic	RCV000231947	SCV000323105	likely benign	Hypercholesterolemia, familial, 1	2016-08-31	criteria provided, single submitter	research	does not meet required criteria
GeneDx	RCV000419458	SCV000521000	benign	not specified	2016-12-07	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.
Fundacion Hipercolesterolemia Familiar	RCV000231947	SCV000607655	uncertain significance	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Color Diagnostics, LLC DBA Color Health	RCV000231947	SCV000689769	benign	Hypercholesterolemia, familial, 1	2017-06-22	criteria provided, single submitter	clinical testing
Robarts Research Institute, Western University	RCV000231947	SCV000782932	likely benign	Hypercholesterolemia, familial, 1	2018-01-02	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000231947	SCV001283055	uncertain significance	Hypercholesterolemia, familial, 1	2017-04-27	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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Genome-Nilou Lab	RCV000231947	SCV001653319	likely benign	Hypercholesterolemia, familial, 1	2021-05-18	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001531890	SCV001747209	likely benign	not provided	2024-08-01	criteria provided, single submitter	clinical testing	LDLR: BP4, BP7
Genetic Services Laboratory, University of Chicago	RCV000419458	SCV002066956	benign	not specified	2019-08-08	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002408958	SCV002717409	benign	Cardiovascular phenotype	2016-01-12	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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001531890	SCV004219966	benign	not provided	2019-02-07	criteria provided, single submitter	clinical testing
GENinCode PLC	RCV000858146	SCV005050214	benign	Familial hypercholesterolemia	2022-07-20	criteria provided, single submitter	clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000231947	SCV000606557	benign	Hypercholesterolemia, familial, 1		no assertion criteria provided	research
Natera, Inc.	RCV000858146	SCV001461324	benign	Familial hypercholesterolemia	2020-09-16	no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000419458	SCV001921408	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001531890	SCV001966251	likely benign	not provided		no assertion criteria provided	clinical testing