ClinVar Miner

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

gnomAD frequency: 0.00025  dbSNP: rs137853962
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Total submissions: 19
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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.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute RCV000606941 SCV006066097 likely benign not specified 2025-04-09 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000058920 SCV005875350 likely benign not provided 2023-12-15 criteria provided, single submitter clinical testing
GENinCode PLC RCV000771316 SCV005619955 likely benign Familial hypercholesterolemia 2025-01-07 criteria provided, single submitter clinical testing This is a synonymous (silent) variant that is not predicted to impact splicing and occurs at a nucleotide which is not highly conserved. This variant has been classified as Likely Benign (BP4, BP7).
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.
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
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.
Labcorp Genetics (formerly Invitae), Labcorp RCV000771316 SCV001003893 likely benign Familial hypercholesterolemia 2025-01-30 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
Robarts Research Institute, Western University RCV000210227 SCV000782930 likely benign Hypercholesterolemia, familial, 1 2018-01-02 criteria provided, single submitter clinical testing
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)
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
LDLR-LOVD, British Heart Foundation RCV000210227 SCV000295733 likely benign Hypercholesterolemia, familial, 1 2016-03-25 criteria provided, single submitter literature only
Cardiovascular Biomarker Research Laboratory, Mayo Clinic RCV000210227 SCV000266308 likely benign Hypercholesterolemia, familial, 1 2015-08-31 criteria provided, single submitter research MAF =<0.3%
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).
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000058920 SCV001963433 likely benign not provided no assertion criteria provided clinical testing
Clinical Genetics, Academic Medical Center RCV000606941 SCV001920580 benign not specified no assertion criteria provided clinical testing
Natera, Inc. RCV000771316 SCV001453898 likely benign Familial hypercholesterolemia 2020-01-02 no assertion criteria provided clinical testing
SNPedia RCV000058920 SCV000090441 not provided not provided no assertion provided not provided

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