Submissions for variant NM_000527.5(LDLR):c.1194C>T (p.Ile398=)

gnomAD frequency: 0.00138  dbSNP: rs13306498

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000210233	SCV002817131	likely benign	Hypercholesterolemia, familial, 1	2022-08-29	reviewed by expert panel	curation	The NM_000527.5(LDLR): c.1194C>T (p.Ile398=) variant is classified as Likely Benign for Familial Hypercholesterolemia by applying evidence code BS1, 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). The supporting evidence is as follows: BS1 - FAF = 0.00448 (0.448%) in East Asian exomes (gnomAD v2.1.1). BP4 - No REVEL, splicing evaluation required. Functional data on splicing not available. Variant is not located within the limits of canonical splicing sites Variant is exonic and at least 50bp upstream from canonical donor site but does not creates AG There is no AG Nearby Variant is not predicted to alter splicing. BP7 - Variant is synonymous and meets BP4
Cardiovascular Biomarker Research Laboratory, Mayo Clinic	RCV000210233	SCV000266323	likely benign	Hypercholesterolemia, familial, 1	2016-08-31	criteria provided, single submitter	research	MAF =<0.3%
LDLR-LOVD, British Heart Foundation	RCV000210233	SCV000295287	benign	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Labcorp Genetics (formerly Invitae), Labcorp	RCV000858408	SCV000556771	benign	Familial hypercholesterolemia	2025-01-19	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000210233	SCV000689759	benign	Hypercholesterolemia, familial, 1	2017-07-17	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000210233	SCV001286368	benign	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). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Pars Genome Lab	RCV000210233	SCV001736823	likely benign	Hypercholesterolemia, familial, 1	2021-05-18	criteria provided, single submitter	clinical testing
GeneDx	RCV001723783	SCV001949524	benign	not provided	2020-01-09	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 17347910, 32719484)
CeGaT Center for Human Genetics Tuebingen	RCV001723783	SCV002063727	likely benign	not provided	2024-10-01	criteria provided, single submitter	clinical testing	LDLR: BP4, BP7, BS1
Ambry Genetics	RCV002336587	SCV002644824	likely benign	Cardiovascular phenotype	2016-05-13	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	RCV001699012	SCV005204652	benign	not specified	2024-06-19	criteria provided, single submitter	clinical testing	Variant summary: LDLR c.1194C>T alters a non-conserved nucleotide resulting in a synonymous change. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0017 in 250716 control chromosomes, predominantly at a frequency of 0.0053 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 4 fold of the estimated maximal expected allele frequency for a pathogenic variant in LDLR causing Familial Hypercholesterolemia phenotype (0.0013). c.1194C>T has been reported in the literature in individuals affected with Familial Hypercholesterolemia (e.g. Al-Khateeb_2011, Komarova_2013) without evidence for causality. These report(s) do not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. Co-occurrences with other pathogenic variant(s) have been reported (LDLR, p. Ser65Glyfs*64; LDLR, p. Trp562Cysfs*5), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 21418584, 24373485). ClinVar contains an entry for this variant (Variation ID: 224620). Based on the evidence outlined above, the variant was classified as benign.
GENinCode PLC	RCV000858408	SCV005387567	benign	Familial hypercholesterolemia	2024-10-17	criteria provided, single submitter	clinical testing	BA1
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000210233	SCV000583803	likely pathogenic	Hypercholesterolemia, familial, 1	2017-03-30	flagged submission	clinical testing
Natera, Inc.	RCV001272182	SCV001453897	benign	Autosomal dominant familial hypercholesterolemia	2020-05-30	no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV001699012	SCV001920104	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001723783	SCV001969926	likely benign	not provided		no assertion criteria provided	clinical testing