ClinVar Miner

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

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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000211628 SCV000295967 likely pathogenic Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge RCV000211628 SCV000323009 uncertain significance Familial hypercholesterolemia 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 Familial hypercholesterolemia 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 Familial hypercholesterolemia 1 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 1 2017-03-30 criteria provided, single submitter clinical testing
Laboratory of Genetics and Molecular Cardiology, University of São Paulo RCV000211628 SCV000588657 likely pathogenic Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
GeneDx RCV000497399 SCV000589577 pathogenic not provided 2020-10-05 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Reported as pathogenic/likely pathogenic in ClinVar but additional evidence is not available (ClinVar Variant ID#226393; Landrum et al., 2016); In silico protein predictors support that this variant does not alter protein structure/function; At the mRNA level, this nucleotide substitution occurs in the last nucleotide position of exon 16, which is conserved across species, and may affect the splice donor site; functional studies support that this variant results in abnormal splicing, though the precise aberrant splice outcome was not characterized (Mak et al., 1998); 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); This variant is associated with the following publications: (PMID: 16314194, 30526649, 9763532, 7649549, 11810272, 12436241, 19446849, 28104544, 28169869, 29233637, 27816806, 23375686, 21310417, 19318025, 20145306, 20538126, 15199436, 22859806, 22698793, 15701167, 18718593, 29874871, 27821657, 31491741, 31447099, 32977124, 32331935)
Fundacion Hipercolesterolemia Familiar RCV000211628 SCV000607696 uncertain significance Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
Invitae RCV000587818 SCV000627033 pathogenic Familial hypercholesterolemia 2020-09-20 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.
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, Partners HealthCare Personalized Medicine RCV000844752 SCV000731742 pathogenic Homozygous familial hypercholesterolemia 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.
Iberoamerican FH Network RCV000211628 SCV000748063 uncertain significance Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
Color Health, Inc 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 Familial hypercholesterolemia 1 2021-05-24 criteria provided, single submitter clinical testing Affects splicing, IVS16 ds -1 G>A.
Cardiovascular Genetics Laboratory,PathWest Laboratory Medicine WA - Fiona Stanley Hospital RCV000211628 SCV000268666 pathogenic Familial hypercholesterolemia 1 2013-04-12 no assertion criteria provided clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000211628 SCV000606634 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research

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