ClinVar Miner

Submissions for variant NM_000527.4(LDLR):c.2389G>A (p.Val797Met) (rs750518671)

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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Cardiovascular Genetics Laboratory,PathWest Laboratory Medicine WA - Fiona Stanley Hospital RCV000211628 SCV000268666 pathogenic Familial hypercholesterolemia 2013-04-12 no assertion criteria provided clinical testing
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge RCV000211628 SCV000323009 uncertain significance Familial hypercholesterolemia 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 Familial hypercholesterolemia 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
Color RCV000587818 SCV000904109 pathogenic Familial hypercholesterolemias 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.
Fundacion Hipercolesterolemia Familiar RCV000211628 SCV000607696 uncertain significance Familial hypercholesterolemia 2016-03-01 criteria provided, single submitter research
GeneDx RCV000497399 SCV000589577 pathogenic not provided 2018-08-21 criteria provided, single submitter clinical testing The V797M pathogenic variant in the LDLR gene (referred to as V776M due to the use of alternative nomenclature) was initially reported in a large family with FH and was found to segregate with disease in multiple affected individuals (Pereira et al., 1995). This variant was subsequently described in numerous other individuals with FH (Mak et al., 1998, Fouchier et al., 2001; Amsellem et al., 2002; Leren et al., 2004; Zakharova et al., 2005; Robles-Osorio et al., 2006; Miyake et al., 2009; Alonso et al., 2009; Guardamagna et al., 2009; Chiou et al., 2010; Chmara et al., 2010; Ho et al., 2012; Tichy et al., 20120; Bertolini et al., 2013), including a 17 year-old female with atherosclerotic cardiovascular disease who was also found to carry two additional variants in FH-associated genes (Setia et al., 2016). Ma et al. (2017) reported homozygous V797M in a Chinese male FH patient with cardiovascular disease, xanthomas, arcus, and extremely elevated LDL-C levels. In addition, V797M is not observed at a significant frequency in large population cohorts (Lek et al., 2016) and is described in ClinVar as likely pathogenic or pathogenic by multiple other clinical laboratories (SCV000540866.1, SCV000503482.1, SCV000583945.1, SCV000627033.2, SCV000697227.1, SCV000731742.1, SCV000268666.1; Landrum et al., 2016).This variant could be functionally significant at the mRNA or protein levels. At the mRNA level, the c.2389G>A nucleotide substitution occurs in the last position of exon 16, a position that may affect the splice donor site. Guanine (G) is conserved across species at this nucleotide position, and functional studies support that this variant results in abnormal splicing, though the precise aberrant splice outcome was not characterized (Mak et al., 1998). Functional splice studies of a different variant at this same nucleotide position (c.2389 G>T, p.V797L) demonstrate c.2389 G>T results in skipping of exon 16, further supporting the functional importance of this nucleotide position (Bourbon et al., 2009). Moreover, c.2389 G>T has been reported as a pathogenic variant in association with FH in the published literature and by another clinical laboratory in ClinVar (Lombardi et al., 2000; Bourbon et al., 2009; ClinVar SCV000583946.1; Landrum et al., 2016). At the protein level, in silico analyses, including protein predictors and evolutionary conservation, support that V797M does not alter protein structure/function. Nevertheless, Guardamagna, et al. (2009) described this variant as resulting in residual receptor activity in cultured fibroblasts of FH heterozygotes as </= 50%, though functional data were not presented in that study.
Iberoamerican FH Network RCV000211628 SCV000748063 uncertain significance Familial hypercholesterolemia 2016-03-01 criteria provided, single submitter research
Integrated Genetics/Laboratory Corporation of America RCV000587818 SCV000697227 pathogenic Familial hypercholesterolemias 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.
Invitae RCV000587818 SCV000627033 pathogenic Familial hypercholesterolemias 2018-11-06 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 797 of the LDLR protein (p.Val797Met). The valine residue is weakly conserved and there is a small physicochemical difference between valine and methionine. This variant also falls at the last nucleotide of exon 16 of the LDLR coding sequence, which is part of the consensus splice site for this exon. Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098). This variant is present in population databases (rs750518671, ExAC 0.006%). This variant has been reported to segregate with familial hypercholesterolemia in a family (PMID: 7649549) and has been observed in multiple unrelated individuals and families affected with hypercholesterolemia (PMID: 23375686, 19446849, 22698793, 22859806, 20145306, 9763532). This variant is also known as p.Val776Met in the literature. ClinVar contains an entry for this variant (Variation ID: 226393). Experimental studies have shown that this missense change leads to a splicing defect (PMID: 9763532). A different variant affecting this nucleotide (c.2389G>T) has been determined to be pathogenic (PMID: 10735632 , 18325082, 19411563). This suggests that this nucleotide is important for normal RNA splicing, and that other variants at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
LDLR-LOVD, British Heart Foundation RCV000211628 SCV000295967 likely pathogenic Familial hypercholesterolemia 2016-03-25 criteria provided, single submitter literature only
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000211628 SCV000606634 pathogenic Familial hypercholesterolemia no assertion criteria provided research
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000844752 SCV000731742 pathogenic Familial hypercholesterolemia - homozygous 2017-08-07 criteria provided, single submitter clinical testing The p.Val797Met variant in LDLR has been reported in the heterozygous, homozygou s, or compound heterozygous state in >10 individuals with familial hypercholeste rolemia (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) and has been identified in 1/30782 South Asian chromosomes by gnomAD (http://gnomad .broadinstitute.org). This variant is located in the last base of the exon, whic h is part of the 5? splice region and has been shown to cause altered splicing l eading to absent protein (Mak 1998). Heterozygous loss of function of the LDLR g ene is an established disease mechanism in FH. In summary, this variant meets cr iteria to be classified as pathogenic for familial hypercholesterolemia in an au tosomal dominant manner based upon presence in affected individuals, segregation studies, low frequency in the general population, and the demonstrated impact t o the protein. ACMG/AMP criteria applied: PP1_Strong, PM2, PS3_Moderate, PS4_Mod erate.
Laboratory of Genetics and Molecular Cardiology,University of São Paulo RCV000211628 SCV000588657 likely pathogenic Familial hypercholesterolemia 2016-03-01 criteria provided, single submitter research
Molecular Genetics Laboratory,Centre for Cardiovascular Surgery and Transplantation RCV000211628 SCV000540866 likely pathogenic Familial hypercholesterolemia 2016-11-05 criteria provided, single submitter clinical testing
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000211628 SCV000583945 pathogenic Familial hypercholesterolemia 2017-03-30 criteria provided, single submitter clinical testing

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