Submissions for variant NM_000527.5(LDLR):c.2311G>A (p.Ala771Thr)

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory of Genetics and Molecular Cardiology, University of São Paulo	RCV000497031	SCV000588646	uncertain significance	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV001856995	SCV002200678	pathogenic	Familial hypercholesterolemia	2025-01-12	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 771 of the LDLR protein (p.Ala771Thr). This variant also falls at the last nucleotide of exon 15, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 26802169, 37813054; internal data). Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this LDLR variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 363,995 individuals referred to our laboratory for LDLR testing. ClinVar contains an entry for this variant (Variation ID: 431545). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Mendelics	RCV000497031	SCV002517561	pathogenic	Hypercholesterolemia, familial, 1	2022-05-04	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001856995	SCV004359068	uncertain significance	Familial hypercholesterolemia	2022-04-05	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Ala750Thr in the mature protein) replaces alanine with threonine at codon 771 of the LDLR protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). However, this variant causes a G>A nucleotide substitution at the last nucleotide of exon 15 of the LDLR gene, and splice site prediction tools suggest that this variant may have significant impact on the RNA splicing. A mini-gene splicing assay has shown that this variant causes complete abolition of the natural splice site and exclusive use of two cryptic splice sites at c.2311+90 and at c.2190 (PMID: 26802169). This variant has been reported in an individual affected with hypercholesterolemia (PMID: 26802169). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001856995	SCV005076167	likely pathogenic	Familial hypercholesterolemia	2024-04-15	criteria provided, single submitter	clinical testing	Variant summary: LDLR c.2311G>A (p.Ala771Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Three predict the variant weakens a canonical 5' donor site and one predicts the variant abolishes this site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Wintjens_2016). The variant was absent in 250596 control chromosomes (gnomAD). c.2311G>A has been reported in the literature in individuals affected with Familial Hypercholesterolemia (e.g. Wintjens_2016, Albuquerque_2023). These data indicate that the variant may be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 26802169, 37813054). ClinVar contains an entry for this variant (Variation ID: 431545). Based on the evidence outlined above, the variant was classified as likely pathogenic.
All of Us Research Program, National Institutes of Health	RCV000497031	SCV005427651	uncertain significance	Hypercholesterolemia, familial, 1	2024-05-09	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Ala750Thr in the mature protein) replaces alanine with threonine at codon 771 of the LDLR protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). However, this variant causes a G>A nucleotide substitution at the last nucleotide of exon 15 of the LDLR gene, and splice site prediction tools suggest that this variant may have significant impact on the RNA splicing. A mini-gene splicing assay has shown that this variant causes complete abolition of the natural splice site and exclusive use of two cryptic splice sites at c.2311+90 and at c.2190 (PMID: 26802169). This variant has been reported in an individual affected with hypercholesterolemia (PMID: 26802169). 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.