Submissions for variant NM_000527.5(LDLR):c.1875C>T (p.Asn625=)

gnomAD frequency: 0.00026  dbSNP: rs137853962

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000210227	SCV004022434	likely benign	Hypercholesterolemia, familial, 1	2023-04-28	reviewed by expert panel	curation	The NM_000527.5(LDLR):c.1875C>T (p.Asn625=) variant is classified as Likely Benign for Familial Hypercholesterolemia by applying evidence codes PP1, BP2, BP4, and BP7 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). Variant has 3 supporting evidence codes towards Benign, enough to classify as Likely benign, and only 1 supporting evidence codes towards Pathogenic. The Benign criteria overwhelms the Pathogenic criteria, so we are confident in classifying this variant as Likely benign. The supporting evidence is as follows: PP1: Variant segregates with FH phenotype in 2 informative meioses in 1 families from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge. So PP1 is met. BP2: 1 individual from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge with LDLR c.1598G>A. Phenotype LDL 168mg/dl under statins - Htz phenotype, c.1598G>A - Pathogenic by these guidelines. BP4: No REVEL available, splicing evaluation needed. Functional data on splicing not available. A) variant not on limits. B) variant is exonic and at least 50bp upstream from the canonical donor site, but it does not create AG. C) there is an AG nearby. MES scores: variant cryptic = -1.41, wt cryptic = -2.30, canonical acceptor = 9.58. Ratio variant cryptic/wt cryptic: -1.41/-2.30 = 0.61 --- it is not above 1.1 Ratio variant cryptic/canonical acceptor: -1.41/9.58 = 0.15--- it is not above 0.9 Variant is not predicted to alter splicing. So BP4 is met. BP7: Variant is synonymous and meets BP4.
Cardiovascular Biomarker Research Laboratory, Mayo Clinic	RCV000210227	SCV000266308	likely benign	Hypercholesterolemia, familial, 1	2015-08-31	criteria provided, single submitter	research	MAF =<0.3%
LDLR-LOVD, British Heart Foundation	RCV000210227	SCV000295733	likely benign	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	RCV000210227	SCV000322983	likely benign	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research	0/95 non-FH individuals
GeneDx	RCV000058920	SCV000730512	likely benign	not provided	2021-01-04	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 22881376, 18065781, 17347910, 25985138)
Robarts Research Institute, Western University	RCV000210227	SCV000782930	likely benign	Hypercholesterolemia, familial, 1	2018-01-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000771316	SCV000903574	likely benign	Familial hypercholesterolemia	2017-07-07	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000771316	SCV001003893	likely benign	Familial hypercholesterolemia	2024-02-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000210227	SCV001283053	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). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000606941	SCV001360704	likely benign	not specified	2019-10-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002408569	SCV002717831	likely benign	Cardiovascular phenotype	2016-03-10	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
SNPedia	RCV000058920	SCV000090441	not provided	not provided		no assertion provided	not provided
Natera, Inc.	RCV000771316	SCV001453898	likely benign	Familial hypercholesterolemia	2020-01-02	no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000606941	SCV001920580	benign	not specified		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000058920	SCV001963433	likely benign	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003944982	SCV004759583	likely benign	LDLR-related disorder	2023-11-30	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).