Submissions for variant NM_000527.5(LDLR):c.1429G>A (p.Asp477Asn)

dbSNP: rs780316072

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000237250	SCV000295426	uncertain significance	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Robarts Research Institute, Western University	RCV000237250	SCV000782914	uncertain significance	Hypercholesterolemia, familial, 1	2018-01-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001177032	SCV000917578	likely pathogenic	Familial hypercholesterolemia	2024-12-10	criteria provided, single submitter	clinical testing	Variant summary: LDLR c.1429G>A (p.Asp477Asn) results in a conservative amino acid change located in the LDL-receptor class B (LDLRB) repeat profile domain (IPR051221) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251116 control chromosomes. c.1429G>A has been reported in the literature in individuals affected with or suspected of Familial Hypercholesterolemia (e.g., Alnouri_2022, Cao_2021, Dron_2020, Fouchier_2005, Jawabri_2024, Morad_2018, Rimbert_2021, Trinder_2019, Labcorp (formerly Invitae)). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (e.g., Jawabri_2024). The most pronounced variant effect resulted in a 70-75% reduction of Dil-LDL internalization compared to wild-type in CHO-ldlA7 cell line experiments. The following publications have been ascertained in the context of this evaluation (PMID: 35249492, 36338372, 32041611, 16250003, 39114568, 29172679, 35047021, 31345425). ClinVar contains an entry for this variant (Variation ID: 251838). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV001177032	SCV001341141	uncertain significance	Familial hypercholesterolemia	2019-05-03	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Asp456Asn in the mature protein) replaces aspartic acid with asparagine at codon 477 of the LDLR protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in an individual affected with familial hypercholesterolemia (PMID: 16250003). This variant has been identified in 1/251116 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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.
Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia	RCV000237250	SCV001432631	uncertain significance	Hypercholesterolemia, familial, 1	2019-05-13	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV001177032	SCV003257838	pathogenic	Familial hypercholesterolemia	2024-05-22	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 477 of the LDLR protein (p.Asp477Asn). This variant is present in population databases (rs780316072, gnomAD 0.006%). This missense change has been observed in individuals with clinical features of familial hypercholesterolemia (PMID: 16250003, 29172679, 31345425, 35249492; Invitae). ClinVar contains an entry for this variant (Variation ID: 251838). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV003329271	SCV004036895	uncertain significance	not provided	2023-08-03	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18325082, 33740630, 32041611, 35249492, 22220933, 29172679, 16250003, 31345425, 35047021)
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV000237250	SCV004807780	uncertain significance	Hypercholesterolemia, familial, 1	2024-03-29	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000237250	SCV005427605	uncertain significance	Hypercholesterolemia, familial, 1	2024-07-20	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with asparagine at codon 477 of the LDLR protein. This variant is also known as p.Asp456Asn in the mature protein. This variant alters a conserved aspartic acid residue in the LDLR type B repeat 2 of the LDLR protein (a.a. 439 - 485), 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. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in several individuals affected with familial hypercholesterolemia (PMID: 16250003, 29172679, 31345425, 35047021, 35249492). One of these individuals also carried a likely pathogenic variant in the PCSK9 gene (PMID: 35047021). In one family, this variant was identified in several unaffected family members (PMID: 35249492). This variant has been identified in 1/251116 chromosomes 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.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000237250	SCV000606421	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research
Natera, Inc.	RCV001177032	SCV002086424	uncertain significance	Familial hypercholesterolemia	2020-12-11	no assertion criteria provided	clinical testing