Submissions for variant NM_000527.5(LDLR):c.680_681del (p.Asp227fs)

dbSNP: rs387906305

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000003929	SCV000294896	pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Robarts Research Institute, Western University	RCV000003929	SCV000484796	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	RCV000003929	SCV000503211	pathogenic	Hypercholesterolemia, familial, 1	2016-12-16	criteria provided, single submitter	clinical testing	subject mutated among 2600 FH index cases screened = 1 , family member = 1 with co-segregation
Athena Diagnostics	RCV000517763	SCV000614009	pathogenic	not provided	2017-06-07	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000844736	SCV000713116	pathogenic	Homozygous familial hypercholesterolemia	2019-05-08	criteria provided, single submitter	clinical testing	The p.Asp227fs variant in LDLR has been reported in at least 9 individuals with hypercholesterolemia (Gudnason 1993, Graham 1999, Bunn 2002, Dedoussis 2004, Martin 2016) and has also been reported in ClinVar (Variation ID #3731). This variant has also been identified in 1/110684 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs387906305). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 227 and leads to a premature termination codon 12 amino acids downstream. 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 mechanism in familial hypercholesterolemia (FH). In summary, this variant meets criteria to be classified as pathogenic for FH in an autosomal dominant manner based upon the predicted impact to the protein, presence in multiple affected individuals and low frequency in controls. ACMG/AMP Criteria applied: PVS1, PM2, PS4_Moderate.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001201362	SCV000752414	pathogenic	Familial hypercholesterolemia	2024-11-18	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asp227Glyfs*12) 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 (rs387906305, gnomAD 0.0009%). This premature translational stop signal has been observed in individuals with familial hypercholesterolemia (FH) (PMID: 8093663, 11857755, 14974088, 27765764). Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this LDLR variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 363,995 individuals referred to our laboratory for LDLR testing. This variant is also known as 679-680delAC and p.D206fs. ClinVar contains an entry for this variant (Variation ID: 3731). For these reasons, this variant has been classified as Pathogenic.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000003929	SCV000839991	pathogenic	Hypercholesterolemia, familial, 1	2017-05-25	criteria provided, single submitter	clinical testing	The c.680_681del (p.Asp227Glyfs*12) variant in the LDLR gene has been detected in multiple patients with hypercholesterolemia [PMID 8093663, 14974088, 10559517]. This 2 bp deletion in exon 4 results in a frameshift and the creation of a premature stop codon. This variant is thus predicted to result in a loss of function of the protein. This variant is rare and has not been detected in the ExAC database. This variant thus classified as pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000517763	SCV001469535	pathogenic	not provided	2020-07-22	criteria provided, single submitter	clinical testing	The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and not found in general population data.
Ambry Genetics	RCV002362559	SCV002664085	pathogenic	Cardiovascular phenotype	2024-08-07	criteria provided, single submitter	clinical testing	The c.680_681delAC pathogenic mutation, located in coding exon 4 of the LDLR gene, results from a deletion of two nucleotides at nucleotide positions 680 to 681, causing a translational frameshift with a predicted alternate stop codon (p.D227Gfs*12). This alteration has been detected in individuals from cohorts with confirmed or suspected familial hypercholesterolemia (Gudnason V et al. Arterioscler Thromb. 1993;13:56-63; Graham CA et al. Atherosclerosis. 1999;147:309-16; Dedoussis GV et al. Hum Mutat. 2004;23:285-6; Hooper AJ et al. Atherosclerosis. 2012;224:430-4; Futema M et al. Atherosclerosis. 2017;260:47-55). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
GeneDx	RCV000517763	SCV002817896	pathogenic	not provided	2022-06-30	criteria provided, single submitter	clinical testing	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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 8093663, 31447099, 32770674, 32041611, 33087929, 34037665)
Genetics and Molecular Pathology, SA Pathology	RCV000003929	SCV004175600	pathogenic	Hypercholesterolemia, familial, 1	2023-06-02	criteria provided, single submitter	clinical testing	The LDLR c.680_681del variant is classified as Pathogenic (PVS1, PS4_Moderate, PM2) This LDLR c.680_681del variant is located in exon 4/18 and is predicted to cause a shift in the reading frame at codon 227 introducing a premature termination codon 12 amino acids downstream. (PVS1) The variant has been reported in multiple probands with a clinical presentation of hypercholesterolaemia (PMID: 27680772 , 22883975, 23669246, 14974088) (PS4_Moderate). This variant is absent from population databases (PM2). The variant has been reported in dbSNP (rs387906305) and in the HGMD database: CD931019. It has been reported as Pathogenic/Likely pathogenic by other diagnostic laboratories (ClinVar Variation ID: 3731).
Revvity Omics, Revvity	RCV000003929	SCV004237257	pathogenic	Hypercholesterolemia, familial, 1	2023-02-13	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000003929	SCV005426462	pathogenic	Hypercholesterolemia, familial, 1	2024-08-31	criteria provided, single submitter	clinical testing	The c.680_681del (p.Asp227Glyfs*12) variant in the LDLR gene, that encodes for low density lipoprotein receptor, introduces a premature translation termination codon resulting in an absent or disrupted protein product. This variant has been reported in several unrelated individuals (>10) affected with familial hypercholesterolemia (FH) (PMID:14974088, 10559517, 11857755, 27765764, 8093663, 27680772, 22883975, 23669246). Loss-of-function variants in LDLR are well known to be pathogenic and ClinGen score shows sufficient evidence of haploinsufficiency of this gene (PMID: 33740630, 15321837, 20809525, 28645073). Truncating variants downstream of this variant are reported to be pathogenic in the literature (PMID:15701167, 31491741, 28028493) and by several ClinVar submitters (ClinVar ID: 251465, 251436). This variant is found to be rare (1/248472; 0.0004025%) in the general population database, gnomAD and interpreted as pathogenic by multiple submitters in the ClinVar (ClinVar ID: 3731). Therefore, the c.680_681del (p.Asp227Glyfs*12) variant in the LDLR gene is classified as pathogenic.
OMIM	RCV000003929	SCV000024094	pathogenic	Hypercholesterolemia, familial, 1	1993-01-01	no assertion criteria provided	literature only
Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	RCV000003929	SCV000268579	pathogenic	Hypercholesterolemia, familial, 1	2008-06-09	no assertion criteria provided	clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000003929	SCV000606195	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000517763	SCV000925127	pathogenic	not provided	2017-12-15	no assertion criteria provided	provider interpretation	p.Asp227Glyfs*12 (c.680_681delAC) in exon 4 of the LDLR gene (NM_000527.4; chr19-11216262-AC-) This variant is also known as 79-680delAC and p.D206fs in the literature. SCICD Classification: pathogenic variant based on mechanism of disease, strong case data and rarity in the general population. We do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Gene-level evidence: LDLR: LDL receptors are located on the surface of the liver and play an important role in LDL recycling. Pathogenic variants in LDLR account for 80% of cases of familial hypercholesterolemia. Both missense and truncating/frameshift variants can be pathogenic. Case data (not including our patient): at least 6 patients with FH. ClinVar: Classified as pathogenic or likely pathogenic by 5 labs: LDLR-LOVD, British Heart Foundation, Robarts Research Institute,University of Western Ontario, Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies,APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix, m voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum, CardiovasLaboratoriucular Genetics Laboratory,PathWest Laboratory Medicine WA - Fiona Stanley Hospital. Cases in the literature: Gudnason et al., 1993: 3 out of 200 patients with FH (2 of British origin, 1 Afrikaaner) Dedoussis et al., 2004: 1 out of 200 patients with FH (ancestry unclear - 100 German and 100 Greek patients). Wang et al., 2016: 1 out of 313 patients with FH. Bunn et al., 2002: A very similar deletion (c.679-680delAC) was present in 1 out of 150 patients with FH. Segregation data: none reported Functional data: none reported for this specific variant; however, truncating variants in LDLR are a known mechanism of disease. Conservation data: The asparagine at codon 227 is complete conserved across species. Neighboring amino acids are also completely conserved. Population data: Highest MAF in European population: 0.0009%. The variant was reported online in 1 of 122,394 individuals in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. Specifically, the variant was observed in 1 of 55,342 individuals of European descent (MAF=0.0009). The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in datasets like this so this does not necessarily rule out pathogenicity (Pan et al 2012).