ClinVar Miner

Submissions for variant NC_000019.10:g.11089413C>T

dbSNP: rs879254374
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000237475 SCV000294392 likely pathogenic Hypercholesterolemia, familial, 1 2016-03-25 criteria provided, single submitter literature only
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge RCV000237475 SCV000599302 likely pathogenic Hypercholesterolemia, familial, 1 2016-03-01 criteria provided, single submitter curation
Labcorp Genetics (formerly Invitae), Labcorp RCV001854881 SCV002238412 pathogenic Familial hypercholesterolemia 2023-06-02 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Studies have shown that this variant alters LDLR gene expression (PMID: 7937987). ClinVar contains an entry for this variant (Variation ID: 250955). This variant is also known as C-to-T substitution at position -43. This variant has been observed in individuals with familial hypercholesterolemia (PMID: 7937987, 8664911, 15199436, 15359125, 16250003). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This variant occurs in a non-coding region of the LDLR gene. It does not change the encoded amino acid sequence of the LDLR protein.
Ambry Genetics RCV002379055 SCV002700321 pathogenic Cardiovascular phenotype 2022-03-10 criteria provided, single submitter clinical testing The c.-136C>T pathogenic mutation is located in the 5' untranslated region (5’ UTR) of the LDLR gene. This variant results from a C to T substitution 136 nucleotides upstream from the first translated codon. This variant (also referred to as c.-43C>T) has been detected in several individuals with familial hypercholesterolemia (FH) and has been reported to segregate with hypercholesterolemia in families (Koivisto UM et al. Proc. Natl. Acad. Sci. U.S.A., 1994 Oct;91(22):10526-30; Jensen LG et al. Hum Mutat, 1996;7:82-4; Kim JH et al. Mol Cells, 2004 Aug;18(1):63-70; Fouchier SW et al. Hum Mutat, 2005 Dec;26:550-6; Leren TP et al. Atherosclerosis, 2021 04;322:61-66). Assays performed on cells from an individual with this mutation demonstrated reduced LDL receptor mRNA concentration and reduced LDL binding, internalization, and degradation compared to control cells (Jensen LG et al. Hum Mutat, 1996;7:82-4; Koivisto UM et al. Proc. Natl. Acad. Sci. U.S.A., 1994 Oct;91(22):10526-30). Functional studies indicate that this variant results in impaired promotor activity and reduced transcription levels compared to wild type (Koivisto UM et al. Proc. Natl. Acad. Sci. U.S.A., 1994 Oct;91(22):10526-30; Kircher M et al. Nat Commun, 2019 08;10:3583). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Revvity Omics, Revvity RCV000237475 SCV003819476 pathogenic Hypercholesterolemia, familial, 1 2022-11-29 criteria provided, single submitter clinical testing

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