ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1545C>T (p.Asn515=) (rs147896205)

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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 RCV000237272 SCV000295489 benign Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
Illumina Clinical Services Laboratory,Illumina RCV000237272 SCV000410534 likely benign Familial hypercholesterolemia 1 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Invitae RCV000771546 SCV000752431 benign Familial hypercholesterolemia 2019-12-31 criteria provided, single submitter clinical testing
Color RCV000771546 SCV000904107 benign Familial hypercholesterolemia 2017-07-17 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001193181 SCV001361869 benign not specified 2019-06-03 criteria provided, single submitter clinical testing Variant summary: LDLR c.1545C>T alters a non-conserved nucleotide resulting in a synonymous change. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.002 in 251392 control chromosomes in the gnomAD database, including 7 homozygotes. The observed variant frequency is approximately 1.6 fold of the estimated maximal expected allele frequency for a pathogenic variant in LDLR causing Familial Hypercholesterolemia phenotype (0.0013), strongly suggesting that the variant is benign. c.1545C>T has been reported in the literature in sequencing studies of individuals affected with Familial Hypercholesterolemia (Sharifi_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign (n=3)/likely benign (n=1). Based on the evidence outlined above, the variant was classified as benign.

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