Submissions for variant NM_000527.5(LDLR):c.564C>G (p.Tyr188Ter)

dbSNP: rs121908034

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000003925	SCV000294795	pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Robarts Research Institute, Western University	RCV000003925	SCV000484764	likely pathogenic	Hypercholesterolemia, familial, 1		criteria provided, single submitter	clinical testing
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	RCV000003925	SCV000503182	pathogenic	Hypercholesterolemia, familial, 1	2016-12-16	criteria provided, single submitter	clinical testing	subject mutated among 2600 FH index cases screened = 1/previously described in association with FH
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	RCV000003925	SCV000599335	pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	curation
Labcorp Genetics (formerly Invitae), Labcorp	RCV001186871	SCV000627042	pathogenic	Familial hypercholesterolemia	2022-11-22	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr188*) in the LDLR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525, 28645073). This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 3727). This variant is also known as p.Tyr167*. This premature translational stop signal has been observed in individuals with familial hypercholesterolemia (PMID: 1734722, 8882879). It has also been observed to segregate with disease in related individuals.
Color Diagnostics, LLC DBA Color Health	RCV001186871	SCV001353461	pathogenic	Familial hypercholesterolemia	2018-11-21	criteria provided, single submitter	clinical testing	This variant (also known as Y167X and as FH Druze) changes 1 nucleotide in exon 4 of the LDLR gene, creating a premature translation stop signal. This variant has been reported in multiple individuals affected with familial hypercholesterolemia (PMID: 1734722, 8882879, 17142622) and shown to segregate with disease in 6 individuals in a family of Druze origin (PMID: 1734722). An experimental study has shown that no LDLR protein was detectable in cells obtained from an individual homozygous for this variant (PMID: 1734722). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of LDLR function is a known mechanism of disease. Based on available evidence, this variant is classified as Pathogenic.
Ambry Genetics	RCV002345225	SCV002652334	pathogenic	Cardiovascular phenotype	2021-09-30	criteria provided, single submitter	clinical testing	The p.Y188* pathogenic mutation (also known as c.564C>G), located in coding exon 4 of the LDLR gene, results from a C to G substitution at nucleotide position 564. This changes the amino acid from a tyrosine to a stop codon within coding exon 4. This mutation (also referred to as Y167*, Stop 167, and FH-Druze) has been detected in several individuals with familial hypercholesterolemia and segregated with disease in a family (Landsberger D et al. Am J Hum Genet, 1992 Feb;50:427-33; Humphries SE et al. J Med Genet, 2006 Dec;43:943-9; Dron JS et al. BMC Med Genomics, 2020 02;13:23). In studies of patient cells with this variant, LDL binding and degradation as well as LDL receptor synthesis and processing were significantly reduced or absent compared to controls (Landsberger D et al. Am J Hum Genet, 1992 Feb;50:427-33). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV004017227	SCV004847646	pathogenic	Homozygous familial hypercholesterolemia	2019-03-06	criteria provided, single submitter	clinical testing	The p.Tyr188X variant in LDLR has been reported in 1 homozygous individual with severe hypercholesterolemia, 2 heterozygous individuals with hypercholesterolemia, and segregated with disease in 5 affected individuals from 1 family (Landsberger 1992. Humphries 2006). It was absent from large population studies, but is reported in ClinVar (Variation ID: 3727). This nonsense variant leads to a premature termination codon at position 188, which is predicted to lead to a truncated or absent protein. Loss of function of the LDLR gene is an established disease mechanism in autosomal dominant hypercholesterolemia. In vitro functional studies support an impact on protein function (Landsberger 1996). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hypercholesterolemia. ACMG/AMP Criteria applied: PVS1, PM2, PM3, PP1_Moderate, PS3_Supporting, PS4_Supporting.
OMIM	RCV000003925	SCV000024090	pathogenic	Hypercholesterolemia, familial, 1	1992-02-01	no assertion criteria provided	literature only
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000003925	SCV000606160	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research
Rajaie Cardiovascular, Medical and Research Center, Iran University of Medical Sciences	RCV000003925	SCV001467729	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research