Submissions for variant NM_000527.5(LDLR):c.1816G>T (p.Ala606Ser)

gnomAD frequency: 0.00016  dbSNP: rs72658865

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000211562	SCV001960932	uncertain significance	Hypercholesterolemia, familial, 1	2021-06-09	reviewed by expert panel	curation	The NM_000527.5(LDLR):c.1816G>T (p.Ala606Ser) variant is classified as variant of Uncertain significance for Familial Hypercholesterolemia by applying evidence codes (PP1) 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: PP1 - 2 informative meioses identified by Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge.
LDLR-LOVD, British Heart Foundation	RCV000211562	SCV000295675	uncertain significance	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	RCV000211562	SCV000322977	uncertain significance	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research	0/220 non-FH alleles
Robarts Research Institute, Western University	RCV000211562	SCV000484684	uncertain significance	Hypercholesterolemia, familial, 1	2019-08-22	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	RCV000211562	SCV000503417	uncertain significance	Hypercholesterolemia, familial, 1	2016-12-16	criteria provided, single submitter	clinical testing	subjects mutated among 2600 FH index cases screened = 3 / previously described in association with FH/Software predictions: Conflicting
Labcorp Genetics (formerly Invitae), Labcorp	RCV000791434	SCV000627022	uncertain significance	Familial hypercholesterolemia	2021-08-31	criteria provided, single submitter	clinical testing	This sequence change replaces alanine with serine at codon 606 of the LDLR protein (p.Ala606Ser). The alanine residue is highly conserved and there is a moderate physicochemical difference between alanine and serine. This variant is present in population databases (rs72658865, ExAC 0.01%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This missense change has been observed in individual(s) with clinical features of familial hypercholesterolemia (PMID: 9409298, 9544745, 14974088, 15199436, 16250003, 17765246, 18325082, 24956927, 27765764). This variant is also known as p.Arg585Ser. ClinVar contains an entry for this variant (Variation ID: 161264). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change does not substantially affect LDLR function (PMID: 32015373). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color Diagnostics, LLC DBA Color Health	RCV000791434	SCV001347963	uncertain significance	Familial hypercholesterolemia	2023-01-26	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Ala585Ser in the mature protein) replaces alanine with serine at codon 606 of the LDLR protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown that this variant has neutral LDLR expression, LDLR binding and LDL uptake activity compared to wild type, suggesting this variant may not disrupt LDLR function (PMID: 25647241, 32015373). This variant has been reported in multiple individuals affected with familial hypercholesterolemia (PMID: 9409298, 9544745, 14974088, 15199436, 16250003, 17765246, 18325082, 25647241, 27765764). It has also been reported in an individual affected with hypoalphalipoproteinemia (PMID: 35460704). This variant has also been identified in 31/282830 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia	RCV000211562	SCV001432594	uncertain significance	Hypercholesterolemia, familial, 1	2019-06-17	criteria provided, single submitter	research
Mendelics	RCV002247540	SCV002518183	uncertain significance	not specified	2022-05-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002247540	SCV002570636	uncertain significance	not specified	2023-10-24	criteria provided, single submitter	clinical testing	Variant summary: LDLR c.1816G>T (p.Ala606Ser) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-05 in 251476 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in LDLR causing Familial Hypercholesterolemia (8e-05 vs 0.0013), allowing no conclusion about variant significance. c.1816G>T has been reported in the literature in individuals affected with Familial Hypercholesterolemia (e.g. Sun_1997, Leren_2004, Dedoussis_2004, Alves_2021, Dong_2022). These reports do not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (e.g. Thormaehlen_2015, Alves_2021). The following publications have been ascertained in the context of this evaluation (PMID: 34167030, 14974088, 35460704, 15199436, 9409298, 25647241). Thirteen submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Ambry Genetics	RCV002408656	SCV002713071	uncertain significance	Cardiovascular phenotype	2021-12-29	criteria provided, single submitter	clinical testing	The p.A606S variant (also known as c.1816G>T), located in coding exon 12 of the LDLR gene, results from a G to T substitution at nucleotide position 1816. The alanine at codon 606 is replaced by serine, an amino acid with similar properties. This variant has been reported in numerous familial hypercholesterolemia (FH) cohorts; however, limited clinical information was provided (Sun XM et al. Arterioscler Thromb Vasc Biol, 1997 Nov;17:3092-101; Dedoussis GV et al. Hum Mutat, 2004 Mar;23:285-6; Leren TP et al. Semin Vasc Med, 2004 Feb;4:75-85; Fouchier SW et al. Hum Mutat, 2005 Dec;26:550-6; Taylor A et al. Clin Genet, 2007 Jun;71:561-8; Bourbon M et al. Atherosclerosis, 2008 Feb;196:633-42; Leigh SE et al. Ann Hum Genet, 2008 Jul;72:485-98; Norsworthy PJ et al. BMC Med. Genet., 2014 Jun;15:70; Thormaehlen AS et al. PLoS Genet, 2015 Feb;11:e1004855; Medeiros AM et al. Genet Med, 2016 Apr;18:316-24; Wang J et al. Arterioscler Thromb Vasc Biol, 2016 12;36:2439-2445). Additionally, an in vitro study showed this alteration may not impact protein function (Galicia-Garcia U et al. Sci Rep, 2020 02;10:1727). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV000211562	SCV002816858	uncertain significance	Hypercholesterolemia, familial, 1	2021-10-12	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000211562	SCV003814581	uncertain significance	Hypercholesterolemia, familial, 1	2022-09-23	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV000211562	SCV004175364	uncertain significance	Hypercholesterolemia, familial, 1	2022-08-11	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000211562	SCV004822503	uncertain significance	Hypercholesterolemia, familial, 1	2024-08-13	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Ala585Ser in the mature protein) replaces alanine with serine at codon 606 of the LDLR protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown that this variant has neutral LDLR expression, LDLR binding and LDL uptake activity compared to wild type, suggesting this variant may not disrupt LDLR function (PMID: 25647241, 32015373). This variant has been reported in multiple individuals affected with familial hypercholesterolemia (PMID: 9409298, 9544745, 14974088, 15199436, 16250003, 17765246, 18325082, 25647241, 27765764). It has also been reported in an individual affected with hypoalphalipoproteinemia (PMID: 35460704). This variant has also been identified in 31/282830 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
GeneDx	RCV000162003	SCV005201894	uncertain significance	not provided	2024-10-01	criteria provided, single submitter	clinical testing	Observed in multiple unrelated patients tested at GeneDx and in published literature with clinical features of familial hypercholesterolemia; although, detailed clinical and segregation data were not available for many of these probands (PMID: 9409298, 14974088, 15199436, 16250003, 17765246, 24956927, 27765764, 17539906, 18325082); Published functional studies suggest no impact on protein expression or LDL-uptake (PMID: 25647241, 32015373, 34167030); In silico analysis indicates that this missense variant does not alter protein structure/function; Also known as p.(A585S); This variant is associated with the following publications: (PMID: 25637381, 15199436, 24956927, 9544745, 14974088, 17765246, 18325082, 25487149, 16250003, 17539906, 25647241, 9409298, 27765764, 24055113, 32015373, 34167030, 27044878, 32041611, 35460704)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000162003	SCV005625825	likely pathogenic	not provided	2023-10-27	criteria provided, single submitter	clinical testing	The LDLR c.1816G>T (p.Ala606Ser) variant has been reported in the published literature in several individuals and families affected with hypercholesterolemia (PMIDs: 14974088 (2004), 15199436 (2004), 17765246 (2008), 24956927 (2014), 27765764 (2016), 31345425 (2019), 36769678 (2023)). This variant occurred with other variants on the same chromosome (in cis) as part of a complex allele as well as in trans with another deleterious LDLR variant, where the phenotype appeared more severe and is suggestive of homozygous hypercholesterolemia (HoFH) (PMIDs: 26020417 (2016), 27784735 (2016)). Family studies have observed this variant to be associated with disease (PMID: 34167030 (2021)). This variant was also reported in individuals affected with cardiac disease and in controls (PMIDs: 25487149 (2015), 27050191 (2016)). However, functional studies indicate that this variant shows cell surface expression, LDL binding, and LDL uptake activities comparable to the wild-type (PMIDs: 32015373 (2020), 34167030 (2021)). The frequency of this variant in the general population, 0.00043 (22/50804 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as likely pathogenic.
Dept. of Genetics and Pharmacogenomics, Merck Research Labs	RCV000162003	SCV000189578	not provided	not provided		no assertion provided	in vitro
CSER _CC_NCGL, University of Washington	RCV002051657	SCV000190280	likely pathogenic	Hypercholesterolemia	2014-06-01	no assertion criteria provided	research
Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	RCV000211562	SCV000268641	uncertain significance	Hypercholesterolemia, familial, 1	2012-08-07	no assertion criteria provided	clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000211562	SCV000606521	benign	Hypercholesterolemia, familial, 1		no assertion criteria provided	research
Natera, Inc.	RCV000791434	SCV001461320	uncertain significance	Familial hypercholesterolemia	2020-09-16	no assertion criteria provided	clinical testing