Submissions for variant NM_000527.5(LDLR):c.296C>G (p.Ser99Ter)

dbSNP: rs377271627

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000238369	SCV001960958	pathogenic	Hypercholesterolemia, familial, 1	2021-06-07	reviewed by expert panel	curation	The NM_000527.5(LDLR):c.296C>G (p.Ser99Ter) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PVS1, PS4, PM2, PP4 and PS3_Supporting) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PVS1 - Variant is nonsense, causing a stop at codon 99. It is upstream of amino acid 830, so PVS1 is Met. PS4 - Variant meets PM2. Identified in over 20 unrelated clinical FH cases (PMID: 7718019). PM2 - PopMax MAF = 0.000008791 (0.0009%) in european non-finnish exomes (gnomAD v2.1.1). PP4 - Variant meets PM2. Identified in over 20 unrelated clinical FH cases (PMID: 7718019). PS3_supporting - Level 3 assays: PMID 19148831: Epstein-Barr virus transformed lymphocytes from htz patients, FACS and RNA assays - results - ~60% gene expression, LDL-LDLR uptake and protein at cell surface ---- results are below 85% of wild-type, so PS3_supporting is Met
LDLR-LOVD, British Heart Foundation	RCV000238369	SCV000294586	pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Invitae	RCV000775030	SCV000544657	pathogenic	Familial hypercholesterolemia	2023-09-17	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser99*) 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 (rs377271627, gnomAD 0.0009%). This premature translational stop signal has been observed in individuals with familial hypercholesterolemia (PMID: 7718019, 9259195, 9698020, 11857755, 23375686). This variant is also known as p.Ser78* and FH-Svartor. ClinVar contains an entry for this variant (Variation ID: 161269). For these reasons, this variant has been classified as Pathogenic.
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	RCV000238369	SCV000599322	pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	curation
Color Diagnostics, LLC DBA Color Health	RCV000775030	SCV000909127	pathogenic	Familial hypercholesterolemia	2018-08-26	criteria provided, single submitter	clinical testing	Pathogenic variant based on current evidence: This variant changes a single nucleotide in exon 3 of the LDLR gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in over 20 Norwegian individuals affected with familial hypercholesterolemia and is considered a founder mutation in that population (PMID: 7718019). This variant has also been reported in affected individuals in UK, Sweden, Netherlands and New Zealand (PMID: 9259195, 9698020, 11857755, 28964736). This variant is rare in the general population and has been identified in 1/246256 chromosomes 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	RCV002433638	SCV002750122	pathogenic	Cardiovascular phenotype	2021-01-06	criteria provided, single submitter	clinical testing	The p.S99* pathogenic mutation (also known as c.296C>G), located in coding exon 3 of the LDLR gene, results from a C to G substitution at nucleotide position 296. This changes the amino acid from a serine to a stop codon within coding exon 3. Historically referred to as the FH-Svartor allele (or p.S78X), this alteration is considered a Norwegian founder mutation, has been identified in many classic familial hypercholesterolemia (FH) patients, and has been reported to co-segregate with disease in several families (Leren TP et al. Atherosclerosis, 1994 Dec;111:175-82; Day IN et al. Hum. Mutat., 1997;10:116-27; Lind S et al. J. Intern. Med., 1998 Jul;244:19-25; Bunn CF et al. Hum. Mutat., 2002 Mar;19:311). 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.
CSER _CC_NCGL, University of Washington	RCV002051662	SCV000190287	pathogenic	Hypercholesterolemia	2014-06-01	no assertion criteria provided	research
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000238369	SCV000606066	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research