Submissions for variant NM_000527.5(LDLR):c.2389G>A (p.Val797Met)

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000211628	SCV000295967	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	RCV000211628	SCV000323009	uncertain significance	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research	0/150 non-FH alleles; 0/100 healthy control individuals; 0/60 healthy control individuals
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	RCV000211628	SCV000503482	likely pathogenic	Hypercholesterolemia, familial, 1	2016-12-16	criteria provided, single submitter	clinical testing	subjects mutated among 2600 FH index cases screened = 4 , family members = 6/previously described in association with FH/Software predictions: Benign
Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation	RCV000211628	SCV000540866	likely pathogenic	Hypercholesterolemia, familial, 1	2016-11-05	criteria provided, single submitter	clinical testing
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000211628	SCV000583945	pathogenic	Hypercholesterolemia, familial, 1	2017-03-30	criteria provided, single submitter	clinical testing
Laboratory of Genetics and Molecular Cardiology, University of São Paulo	RCV000211628	SCV000588657	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
GeneDx	RCV000497399	SCV000589577	pathogenic	not provided	2023-10-05	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Published function studies demonstrate decreased residual receptor activity in cultured fibroblasts of FH heterozygotes (Guardamagna et al., 2009); Functional splice studies of a different variant at this same nucleotide position (c.2389 G>T, p.V797L) demonstrate skipping of exon 16, further supporting the functional importance of this nucleotide position (Bourbon et al., 2009); Also known as p.(V776M); This variant is associated with the following publications: (PMID: 16314194, 32759540, 30526649, 34037665, 9763532, 7649549, 11810272, 12436241, 28104544, 29233637, 27816806, 23375686, 21310417, 19318025, 20145306, 20538126, 15199436, 22859806, 22698793, 15701167, 18718593, 29874871, 27821657, 31491741, 31447099, 35339733, 34297352, 36229885, 32977124, 32331935, 33740630, 34497632, 35910211, 35913489, 35480308, 28169869, 19446849, 30710474, 33994402, 36991406, 37482509)
Fundacion Hipercolesterolemia Familiar	RCV000211628	SCV000607696	uncertain significance	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Invitae	RCV000587818	SCV000627033	pathogenic	Familial hypercholesterolemia	2024-01-15	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 797 of the LDLR protein (p.Val797Met). This variant also falls at the last nucleotide of exon 16, which is part of the consensus splice site for this exon. This variant is present in population databases (rs750518671, gnomAD 0.003%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 7649549, 9763532, 19446849, 20145306, 22698793, 22859806, 23375686). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 226393). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587818	SCV000697227	pathogenic	Familial hypercholesterolemia	2017-06-21	criteria provided, single submitter	clinical testing	Variant summary: The LDLR c.2389G>A (p.Val797Met) variant involves the alteration of a conserved nucleotide located at the last nucleotide of exon 16. 2/4 in silico tools predict benign outcome for this variant but 5/5 splice prediction tools predict a significant impact on normal splicing. A reverse transcriptionPCR study indicated that it is likely to cause a donor site splicing error (Mak_1998). This variant was found in 1/121374 control chromosomes (including ExAC) at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic LDLR variant (0.0012508). This variant has been found in several FH patients including evidence of cosegregation with disease. Multiple clinical diagnostic laboratories/reputable databases have classified this variant as likely pathogenic/pathogenic. Taken together, this variant is classified as pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000844752	SCV000731742	pathogenic	Homozygous familial hypercholesterolemia	2019-03-29	criteria provided, single submitter	clinical testing	The p.Val797Met variant in LDLR has been reported in the heterozygous, homozygous, or compound heterozygous state in >10 individuals with familial hypercholesterolemia (FH), segregating with disease in at least 15 affected relatives from 4 families (Pereira, 1995, Mak 1998, Tichy 2012, Bertolini 2013, Setia 2016, Leren 2004). This variant has also been reported in Clinvar (Variation ID 226393). This variant has been identified in 1/30782 South Asian chromosomes by the genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs750518671). This variant is located in the last base of the exon, which is part of the 5’ splice region and has been shown to cause altered splicing leading to absent protein (Mak 1998). Heterozygous loss of function of the LDLR gene is an established disease mechanism in FH. In summary, this variant meets our criteria to be classified as pathogenic for familial hypercholesterolemia in an autosomal dominant manner based upon presence in affected individuals, segregation studies, low frequency in the general population and the demonstrated impact to the protein.
Iberoamerican FH Network	RCV000211628	SCV000748063	uncertain significance	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Color Diagnostics, LLC DBA Color Health	RCV000587818	SCV000904109	pathogenic	Familial hypercholesterolemia	2018-05-13	criteria provided, single submitter	clinical testing	Pathogenic variant based on current evidence: This variant (also known as p.Val776Met in the mature protein) changes the last nucleotide in exon 16 of the LDLR mRNA (c.2389G>A). This conserved G at the last nucleotide position of an exon is known to play an important role in splicing. Although detailed splice analysis has not been performed for this variant, one study has indicated that this variant causes splicing defect and leads to absent of transcript (PMID: 9763532). A different variant at the same position (c.2389G>T) has been shown to cause an in-frame skipping of exon 16 that encodes the transmembrane domain of the LDLR protein. This demonstrates the importance of the c.2389G nucleotide in the correct splicing at the exon 16-intron 16 splice region. While this variant is rare in the general population (2/246210 chromosomes in the Genome Aggregation Database, gnomAD), it has been reported in 10+ unrelated individuals affected with familial hypercholesterolemia (PMID: 18718593, 19446849, 20145306, 22698793, 23375686). In addition, this variant has been shown to segregate with disease in 10 members from a Cuban family with familial hypercholesterolemia (PMID: 7649549). Based on available evidence, this variant is classified as Pathogenic.
Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II	RCV000211628	SCV001653660	likely pathogenic	Hypercholesterolemia, familial, 1	2021-05-24	criteria provided, single submitter	clinical testing	Affects splicing, IVS16 ds -1 G>A.
Revvity Omics, Revvity	RCV000211628	SCV002022667	likely pathogenic	Hypercholesterolemia, familial, 1	2023-01-18	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000497399	SCV002047264	pathogenic	not provided	2021-03-08	criteria provided, single submitter	clinical testing	This variant has been reported in multiple index patients with hypercholesterolemia in the published literature (PMID: 31491741 (2019), 23375686 (2013), 22698793 (2012), 20538126 (2010), 20145306 (2010), 18718593 (2009)). One family study indicated the variant strongly segregated with disease (PMID: 7649549 (1995)). In addition, this variant is located at an exon-intron junction and an RT-PCR study suggests the variant may affect LDLR mRNA splicing (PMID: 9763532 (1998)). Based on the available information, this variant is classified as pathogenic.
Ambry Genetics	RCV002453757	SCV002737317	pathogenic	Cardiovascular phenotype	2021-05-20	criteria provided, single submitter	clinical testing	The c.2389G>A pathogenic mutation (also known as p.V797M), located in coding exon 16 of the LDLR gene, results from a G to A substitution at nucleotide position 2389. The amino acid change results in valine to methionine at codon 797, an amino acid with highly similar properties. This change occurs in the last base pair of coding exon 16, which makes it likely to have some effect on normal mRNA splicing. This alteration (also referred to as p.V776M) has been reported in a number of individuals of different origins with familial hypercholesterolemia (Pereira E et al. Hum. Genet., 1995 Sep;96:319-22; Mak YT et al. Arterioscler. Thromb. Vasc. Biol., 1998 Oct;18:1600-5; Fouchier SW et al. Hum. Genet., 2001 Dec;109:602-15; Leren TP et al. Semin Vasc Med, 2004 Feb;4:75-85; Robles-Osorio L et al. Arch. Med. Res., 2006 Jan;37:102-8; Bourbon M et al. Atherosclerosis, 2008 Feb;196:633-42; Alonso R et al. Clin. Biochem., 2009 Jun;42:899-903; Guardamagna O et al. J. Pediatr., 2009 Aug;155:199-204.e2; Chmara M et al. J. Appl. Genet., 2010;51:95-106; Chiou KR et al. Am. J. Cardiol., 2010 Jun;105:1752-8; Setia N et al. Atherosclerosis, 2016 Dec;255:31-36; Durst R et al. Atherosclerosis, 2017 Feb;257:55-63). In addition, this alteration segregated with the disease in a multi-generation family (Pereira E et al. Hum. Genet., 1995 Sep;96:319-22). One study suggested that this alteration would affect the splicing as only the wild type allele was detected by the reverse transcription (Mak YT et al. Arterioscler. Thromb. Vasc. Biol., 1998 Oct;18:1600-5). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Suma Genomics	RCV000211628	SCV004041569	pathogenic	Hypercholesterolemia, familial, 1		criteria provided, single submitter	clinical testing
Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	RCV000211628	SCV000268666	pathogenic	Hypercholesterolemia, familial, 1	2013-04-12	no assertion criteria provided	clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000211628	SCV000606634	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research