Submissions for variant NM_000527.5(LDLR):c.1705G>T (p.Asp569Tyr)

dbSNP: rs879254993

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000237589	SCV000295590	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	RCV000237589	SCV000503390	likely pathogenic	Hypercholesterolemia, familial, 1	2016-12-16	criteria provided, single submitter	clinical testing	subject mutated among 2600 FH index cases screened = 1Other mutation at same codon/software prediction damaging
Ambry Genetics	RCV002401942	SCV002710477	uncertain significance	Cardiovascular phenotype	2018-04-02	criteria provided, single submitter	clinical testing	The c.1705G>T variant (also known as p.D569Y), located in coding exon 11 of the LDLR gene, results from a G to T substitution at nucleotide position 1705. The amino acid change results in aspartic acid to tyrosine at codon 569, an amino acid with highly dissimilar properties. This change occurs in the highly conserved last base pair of coding exon 11, which makes it likely to have some effect on normal mRNA splicing. Using two different splice site prediction tools, this alteration is predicted by ESEfinder to abolish the native splice donor site, but is predicted to weaken (but not abolish) the efficiency of the native splice donor site by BDGP; however, direct evidence is unavailable. This alteration has been reported in a cohort of hypercholesterolemia; however, clinical information was limited (Marduel M et al. Hum. Mutat., 2010 Nov;31:E1811-24). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health	RCV000237589	SCV005427618	uncertain significance	Hypercholesterolemia, familial, 1	2024-07-29	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with tyrosine at codon 569 of the LDLR protein. This variant is also known as p.Asp548Tyr in the mature protein. This variant alters a conserved aspartic acid residue in the LDLR type B repeat 4 of the LDLR protein (a.a. 529-572), where pathogenic missense variants are found enriched (ClinVar-LDLR). Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. This variant causes a G>T nucleotide substitution at the last nucleotide of exon 11 of the LDLR gene, and splice site prediction tools suggest that this variant may impact RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least one individual affected with familial hypercholesterolemia (PMID: 20809525, 21957200). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.