Submissions for variant NM_000527.5(LDLR):c.-188C>T

dbSNP: rs878854023

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000231228	SCV002817119	uncertain significance	Hypercholesterolemia, familial, 1	2022-08-26	reviewed by expert panel	curation	The NM_000527.5 (LDLR):c.-188C>T variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP4, PS4_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: PM2: This variant is absent from gnomAD (gnomAD v2.1.1). PP4: Variant meets PM2 and is identified in >1 index cases who fulfil FH diagnostic criteria after alternative causes of high cholesterol were excluded. PS4_Supporting: Variant meets PM2 and is identified in 2 unrelated index cases who fulfil DLCN criteria for definite FH. One case submitted to ClinVar from U4M - Lille University & CHRU Lille, France; 1 case reported by Fouchier et al, 2005, from Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, The Netherlands.
LDLR-LOVD, British Heart Foundation	RCV000231228	SCV000294365	uncertain significance	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000231228	SCV000583617	pathogenic	Hypercholesterolemia, familial, 1	2017-03-30	criteria provided, single submitter	clinical testing	ACMG Guidelines: Pathogenic (i)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001828107	SCV003516833	likely pathogenic	Familial hypercholesterolemia	2024-11-11	criteria provided, single submitter	clinical testing	This variant occurs in a non-coding region of the LDLR gene. It does not change the encoded amino acid sequence of the LDLR protein. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with familial hypercholesterolemia (PMID: 16250003). Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this LDLR variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 363,995 individuals referred to our laboratory for LDLR testing. ClinVar contains an entry for this variant (Variation ID: 237861). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
GeneDx	RCV003128607	SCV003805466	uncertain significance	not provided	2023-02-22	criteria provided, single submitter	clinical testing	Located in the 5' untranslated region of the LDLR gene and does not create a new start codon or alter the Kozak sequence; Published functional studies show impaired promotor activity (Kircher et al., 2019); This variant is associated with the following publications: (PMID: 16250003, 31395865)
All of Us Research Program, National Institutes of Health	RCV000231228	SCV004818793	uncertain significance	Hypercholesterolemia, familial, 1	2024-03-28	criteria provided, single submitter	clinical testing	This variant is located in the repeat 1 region in the promoter region of the LDLR gene. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 16250003, 35101175). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003128607	SCV005625869	uncertain significance	not provided	2024-04-04	criteria provided, single submitter	clinical testing	The LDLR c.-188C>T variant has been reported in the published literature in an individual affected with familial hypercholesterolemia (FH) (PMID: 16250003 (2005)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant does not affect LDLR mRNA splicing. Based on the available information, we are unable to determine the clinical significance of this variant.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000231228	SCV000605981	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research
Natera, Inc.	RCV001828107	SCV002086351	uncertain significance	Familial hypercholesterolemia	2021-03-12	no assertion criteria provided	clinical testing