Submissions for variant NC_000019.10:g.11089397C>T

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000237330	SCV000294380	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Laboratory of Genetics and Molecular Cardiology, University of São Paulo	RCV000237330	SCV000588474	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV001258114	SCV000752416	pathogenic	Familial hypercholesterolemia	2024-02-01	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 familial hypercholesterolemia (PMID: 10484771, 11005141, 16542394; Invitae). This variant is also known as c.-59C>T. ClinVar contains an entry for this variant (Variation ID: 250945). Studies have shown that this variant alters LDLR gene expression (PMID: 10484771). For these reasons, this variant has been classified as Pathogenic.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV001258114	SCV001434981	likely pathogenic	Familial hypercholesterolemia	2019-04-30	criteria provided, single submitter	clinical testing	The c.-152C>T variant in the LDLR gene sits upstream of the coding region and is predicted to reduce promoter activity of the gene. This variant is not observed in general population databases but has been reported in multiple unrelated individuals with familial hypercholesterolemia (PMID: 11005141, 16542394). Functional studies have shown reduced promoter activity of the LDLR gene when this variant is present (PMID: 10484771). The c.-152C>T variant in the LDLR gene is classified as likely pathogenic.
Ambry Genetics	RCV002401929	SCV002706639	likely pathogenic	Cardiovascular phenotype	2021-03-26	criteria provided, single submitter	clinical testing	The c.-152C>T variant is located in the 5' untranslated region (5’ UTR) of the LDLR gene. This variant results from a C to T substitution 152 bases upstream from the first translated codon. This variant (also described as c.-59C>T) has been reported in individuals with familial hypercholesterolemia (Scholtz CL et al. Hum Mol Genet, 1999 Oct;8:2025-30; Khoo KL et al. Clin Genet, 2000 Aug;58:98-105; Brusgaard K et al. Clin Genet, 2006 Mar;69:277-83). Functional studies showed reduction in promoter activity and transcription (Scholtz CL et al. Hum Mol Genet, 1999 Oct;8:2025-30; Kircher M et al. Nat Commun, 2019 08;10:3583). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
All of Us Research Program, National Institutes of Health	RCV000237330	SCV004836275	likely pathogenic	Hypercholesterolemia, familial, 1	2024-08-30	criteria provided, single submitter	clinical testing	This variant is located in the 5' untranslated region of the LDLR gene. In vitro functional studies have shown that this variant causes a 30-40% reduction in LDLR promoter activity (PMID: 10484771, 31395865). This variant has been reported in more than 10 unrelated individuals affected with familial hypercholesterolemia (PMID: 10484771, 11005141, 16542394, 30293936, 34037665, 34407635). It has been shown that this variant segregates with disease in three affected individuals from one family (PMID: 10484771). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000237330	SCV000605984	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research
Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia	RCV000237330	SCV001432656	uncertain significance	Hypercholesterolemia, familial, 1	2019-03-03	flagged submission	research