Submissions for variant NM_000527.5(LDLR):c.1118_1121dup (p.Tyr375fs)

dbSNP: rs875989916

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000211651	SCV000295228	pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	RCV000211651	SCV000599361	pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	curation
Invitae	RCV000588024	SCV000627012	pathogenic	Familial hypercholesterolemia	2023-10-03	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr375Trpfs*7) 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 present in population databases (no rsID available, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with familial hypercholesterolemia (PMID: 1301956, 20809525, 24075752). This variant is also known as FH Nashville and p.Tyr352fs*7. ClinVar contains an entry for this variant (Variation ID: 226347). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588024	SCV000697184	pathogenic	Familial hypercholesterolemia	2020-02-15	criteria provided, single submitter	clinical testing	Variant summary: LDLR c.1118_1121dupGTGG (p.Tyr375TrpfsX7) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 251364 control chromosomes. c.1118_1121dupGTGG has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (example, Faiz_2013, Vandrovcova_2013, Heath_1999). These data indicate that the variant is likely to be associated with disease. No experimental evidence demonstrating an impact on protein function was ascertained. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Robarts Research Institute, Western University	RCV000211651	SCV000782908	pathogenic	Hypercholesterolemia, familial, 1	2018-01-02	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000825618	SCV000966970	pathogenic	Homozygous familial hypercholesterolemia	2018-02-13	criteria provided, single submitter	clinical testing	The p.Tyr375fs variant has been reported in at least 5 individuals with familial hypercholesterolemia (FH), 4 in the heterozygous state (Day 1997, Humphries 200 6) and 1 in the homozygous state (Hobbs 1992). This variant has also been report ed in ClinVar (Variation ID: 226347). In vitro functional studies provide some e vidence that the p.Tyr375fs variant may impact protein function, resulting in r eceptor activity that <2% compared to wildtype (Hobbs 1992). It has been identif ied in 1/111670 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs875989916). This variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 375 and leads to a premature termination codon 7 amino acids downst ream. This alteration is then predicted to lead to a truncated or absent protein . Heterozygous loss of function of the LDLR gene is an established disease mecha nism in individuals with FH. In summary, this variant meets criteria to be class ified as pathogenic for FH in an autosomal dominant manner based upon the presen ce in multiple affected individuals, functional evidence, very low frequency in the general population and the predicted impact to the protein. ACMG/AMP Criteri a applied (Richards 2015): PVS1, PM2, PS4_Moderate, PS3_Supporting.
Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia	RCV000211651	SCV001432544	likely pathogenic	Hypercholesterolemia, familial, 1	2019-06-05	criteria provided, single submitter	research
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000211651	SCV001754785	pathogenic	Hypercholesterolemia, familial, 1	2019-10-31	criteria provided, single submitter	clinical testing	The c.1118_1121dupGTGG (p.Tyr375Trpfs*7) variant in exon 8 of LDLR gene creates a frameshift and an early stop codon which is predicted to result in an absence of protein product. Loss-of-function variants of LDLR gene are known to cause familial hypercholesterolemia (PMID: 20809525). This variant has been reported in multiple unrelated individuals and families with familial hypercholesterolemia (PMID:301956, 9259195, 16389549, 24075752), but only once in general population database gnomAD. Functional assay of this variant demonstrated that only less than 2% of receptor activity was retained compared to wild type protein (PMID: 1301956). Therefore, the c.1118_1121dupGTGG (p.Tyr375Trpfs*7) variant of LDLR gene is classified as pathogenic.
GeneDx	RCV002284377	SCV002574653	pathogenic	not provided	2022-09-14	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Also known as FH Nashville, 11189 insGTGG*, c.1121_1122insGTGG, p.G353fs; This variant is associated with the following publications: (PMID: 31447099, 34040191, 32719484, 32041611, 22881376, 33303402, 2088165, 9259195, 16389549, 23680767, 31345425, 34037665, 24075752, 10208479, 26582918, 1301956)
Ambry Genetics	RCV002433922	SCV002746507	pathogenic	Cardiovascular phenotype	2022-02-16	criteria provided, single submitter	clinical testing	The c.1118_1121dupGTGG pathogenic mutation, located in coding exon 8 of the LDLR gene, results from a duplication of 4 nucleotides at positions 1118 to 1121, causing a translational frameshift with a predicted alternate stop codon (p.Y375Wfs*7). This duplication has been reported in several individuals presenting with familial hypercholesterolemia (Hobbs HH et al. Annu Rev Genet. 1990;24:133-70; Tosi I et al. Atherosclerosis 2007;194:102-11; Faiz F et al. Atherosclerosis. 2013;230(2):249-55; Defesche JC et al. J Clin Lipidol Sep;11:1338-1346.e7). In addition to the clinical data presented in the literature, 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV002284377	SCV002774351	pathogenic	not provided	2021-08-02	criteria provided, single submitter	clinical testing	The LDLR c.1118_1121dup (p.Tyr375Trpfs*7) variant (also known as FH Nashville) variant alters the translational reading frame of the LDLR mRNA and causes the premature termination of LDLR protein synthesis. The frequency of this variant in the general population, 0.0000088 (1/113680 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in multiple individuals affected with familial hypercholesteremia (PMIDs: 28964736 (2017), 32041611 (2020), 31345425 (2019), 24075752 (2013), 23680767 (2013), 16389549 (2006), 9259195 (1997), 1301956 (1992)). Based on the available information, this variant is classified as pathogenic.
Revvity Omics, Revvity	RCV000211651	SCV003827158	pathogenic	Hypercholesterolemia, familial, 1	2022-06-15	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000588024	SCV004358508	pathogenic	Familial hypercholesterolemia	2022-10-10	criteria provided, single submitter	clinical testing	This variant (also known as FH Nashville in literature) inserts 4 nucleotides in exon 8 of the LDLR gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. Cells from a homozygous individual have shown largely reduced (<2% of wild type) LDLR activity (PMID: 1301956). This variant has been reported in at least 6 unrelated individuals affected with familial hypercholesterolemia (PMID: 1301956, 9259195, 28964736, 34297352). This variant has been identified in 1/251364 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of LDLR function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
OMIM	RCV000211651	SCV000024046	pathogenic	Hypercholesterolemia, familial, 1	1988-11-01	no assertion criteria provided	literature only
Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	RCV000211651	SCV000268600	pathogenic	Hypercholesterolemia, familial, 1	2012-01-31	no assertion criteria provided	clinical testing