Submissions for variant NM_000527.5(LDLR):c.-121T>C

gnomAD frequency: 0.00003  dbSNP: rs777716188

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000211691	SCV000294394	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	RCV000211691	SCV000599303	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	curation
Color Diagnostics, LLC DBA Color Health	RCV000775225	SCV000909470	uncertain significance	Familial hypercholesterolemia	2023-02-22	criteria provided, single submitter	clinical testing	This variant is located in the LDLR protein in the promoter region (between the TATA and SP1 binding motifs) of the LDLR gene. Experimental studies in vitro of LDLR gene expression have shown a moderate decrease in LDLR gene expression (PMID: 25248394, 31395865). However, clinical relevance of this observation is not clear. This variant has been reported in at least two individual affected with familial hypercholesterolemia (PPMID: 22883975, 23669246) and in at least three individuals suspected to be affected with familial hypercholesterolemia (PMID: 20236128, 31345425, 31980526). The genome region of this variant is not well covered in population databases and thus the frequency of this variant in the general population is unknown. 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.
Illumina Laboratory Services, Illumina	RCV000211691	SCV001288136	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.
Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia	RCV000211691	SCV001432551	likely pathogenic	Hypercholesterolemia, familial, 1	2018-12-06	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV000775225	SCV001503764	likely pathogenic	Familial hypercholesterolemia	2024-01-04	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 individuals with clinical features of familial hypercholesterolemia (PMID: 20236128, 24075752, 31345425; Invitae). ClinVar contains an entry for this variant (Variation ID: 226302). Studies have shown that this variant alters LDLR gene expression (PMID: 25248394). 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.
AiLife Diagnostics, AiLife Diagnostics	RCV002223821	SCV002502835	likely pathogenic	not provided	2022-01-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003401126	SCV004119849	likely pathogenic	LDLR-related disorder	2023-03-14	criteria provided, single submitter	clinical testing	The LDLR c.-121T>C variant is located in the 5' untranslated region. This variant has been reported in multiple individuals with Hypercholesterolemia (Taylor et al. 2010. PubMed ID: 20236128; Hooper et al. 2012. PubMed ID: 22883975; Faiz et al. 2013. PubMed ID: 24075752; Trinder et al. 2019. PubMed ID: 31345425. Table S3). Functional study showed that this variant decreases LDLR gene expression (Khamis et al. 2014. PubMed ID: 25248394). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. In ClinVar, this variant has conflicting interpretations of likely pathogenic and uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/). This variant is interpreted as likely pathogenic.
All of Us Research Program, National Institutes of Health	RCV000211691	SCV004819701	uncertain significance	Hypercholesterolemia, familial, 1	2024-01-03	criteria provided, single submitter	clinical testing	This variant is located in the LDLR protein in the promoter region (between the TATA and SP1 binding motifs) of the LDLR gene. Experimental studies in vitro of LDLR gene expression have shown a moderate decrease in LDLR gene expression (PMID: 25248394, 31395865). However, clinical relevance of this observation is not clear. This variant has been reported in at least two individual affected with familial hypercholesterolemia (PPMID: 22883975, 23669246) and in at least three individuals suspected to be affected with familial hypercholesterolemia (PMID: 20236128, 31345425, 31980526). The genome region of this variant is not well covered in population databases and thus the frequency of this variant in the general population is unknown. 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.
Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	RCV000211691	SCV000268532	uncertain significance	Hypercholesterolemia, familial, 1	2011-06-10	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000775225	SCV002086352	uncertain significance	Familial hypercholesterolemia	2021-02-22	no assertion criteria provided	clinical testing