ClinVar Miner

Submissions for variant NM_000527.4(LDLR):c.1118_1121dup (p.Tyr375fs) (rs875989916)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000211651 SCV000295228 pathogenic Familial hypercholesterolemia 2016-03-25 criteria provided, single submitter literature only
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge RCV000211651 SCV000599361 pathogenic Familial hypercholesterolemia 2016-03-01 criteria provided, single submitter curation
Invitae RCV000588024 SCV000627012 pathogenic Familial hypercholesterolemias 2018-12-05 criteria provided, single submitter clinical testing This sequence change inserts 4 nucleotides in exon 8 of the LDLR mRNA (c.1118_1121dupGTGG), causing a frameshift at codon 375. This creates a premature translational stop signal (p.Tyr375Trpfs*7) and is expected to result in an absent or disrupted protein product. Loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525). This particular variant has been reported in the literature in individuals affected with familial hypercholesterolemia (PMID: 1301956, 24075752). This variant is also known as FH Nashville and p.Tyr352fs*7 in the literature. For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000588024 SCV000697184 pathogenic Familial hypercholesterolemias 2016-06-08 criteria provided, single submitter clinical testing Variant summary: The LDLR c.1118_1121dupGTGG (p.Tyr375Trpfs) variant results in a premature termination codon, predicted to cause a truncated or absent LDLR protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. p.Gln384X, p.Cys392X, p.Tyr442X). One in silico tool predicts a damaging outcome for this variant and this variant is absent in 120838 control chromosomes. The variant has been reported in the literature in multiple individuals with diagnosis of FH. In addition, one clinical diagnostic lab has classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Robarts Research Institute,Western University RCV000211651 SCV000782908 pathogenic Familial hypercholesterolemia 2018-01-02 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000825618 SCV000966970 pathogenic Familial hypercholesterolemia - homozygous 2018-02-13 criteria provided, single submitter clinical testing The p.Tyr375fs variant has been reported in at least 5 individuals with familial hypercholesterolemia (FH), 4 in the heterozygous state (Day 1997, Humphries 200 6) and 1 in the homozygous state (Hobbs 1992). This variant has also been report ed in ClinVar (Variation ID: 226347). In vitro functional studies provide some e vidence that the p.Tyr375fs variant may impact protein function, resulting in r eceptor activity that <2% compared to wildtype (Hobbs 1992). It has been identif ied in 1/111670 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs875989916). This variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 375 and leads to a premature termination codon 7 amino acids downst ream. 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 mecha nism in individuals with FH. In summary, this variant meets criteria to be class ified as pathogenic for FH in an autosomal dominant manner based upon the presen ce in multiple affected individuals, functional evidence, very low frequency in the general population and the predicted impact to the protein. ACMG/AMP Criteri a applied (Richards 2015): PVS1, PM2, PS4_Moderate, PS3_Supporting.
Cardiovascular Genetics Laboratory,PathWest Laboratory Medicine WA - Fiona Stanley Hospital RCV000211651 SCV000268600 pathogenic Familial hypercholesterolemia 2012-01-31 no assertion criteria provided clinical testing

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