Submissions for variant NM_000527.5(LDLR):c.1845G>A (p.Glu615=)

gnomAD frequency: 0.00001  dbSNP: rs879255047

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000237596	SCV002817134	uncertain significance	Hypercholesterolemia, familial, 1	2022-08-29	reviewed by expert panel	curation	The NM_000527.5(LDLR):c.1845G>A (p.Glu615=) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2, PP3, and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2: The only >10,000 subpopulation is European (Non-Finnish), in which the variant is absent. So PM2 is met. PP3: No REVEL, splicing evaluation required. Functional data on splicing not available. A) variant located -3 to +6 from canonical donor site MES scores: canonical site variant = -1.8; canonical donor wt = 4.48. Ratio: -1.8/4.48 = -0.4 ---- It is below 0.8. Variant is predicted to alter splicing. So PP3 is met. PP4: Variant meets PM2 and is identified in 1 case fulfilling Simon-Broome criteria for possible FH published in PMID: 17539906 (Taylor et al., 2007). So PP4 is met.
LDLR-LOVD, British Heart Foundation	RCV000237596	SCV000295696	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	RCV000237596	SCV000503422	likely pathogenic	Hypercholesterolemia, familial, 1	2016-12-16	criteria provided, single submitter	clinical testing	subject mutated among 2600 FH index cases screened = 1
Iberoamerican FH Network	RCV000237596	SCV000748155	uncertain significance	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Invitae	RCV001034634	SCV000752417	pathogenic	Familial hypercholesterolemia	2022-09-22	criteria provided, single submitter	clinical testing	This variant is present in population databases (no rsID available, gnomAD 0.01%). This sequence change affects codon 615 of the LDLR mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the LDLR protein. This variant also falls at the last nucleotide of exon 12, which is part of the consensus splice site for this exon. This variant has been observed in individuals with familial hypercholesterolemia (PMID: 17539906; Invitae). For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 252065). This variant is also known as IVS13-2G>A.
Color Diagnostics, LLC DBA Color Health	RCV001034634	SCV001355016	uncertain significance	Familial hypercholesterolemia	2018-12-01	criteria provided, single submitter	clinical testing	Variant of Uncertain Significance due to insufficient evidence: This synonymous variant does not change the amino acid sequence of the LDLR protein. This variant changes the conserved, last nucleotide of exon 12. Computational splicing tools suggest that this variant may adversely impact RNA splicing. To our knowledge, RNA assays have not been performed to investigate this prediction. This variant has been reported in an individual affected with familial hypercholesterolemia (PMID: 17539906). This variant is rare in the general population and has been identified in 1/30958 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
Ambry Genetics	RCV002411096	SCV002717076	uncertain significance	Cardiovascular phenotype	2019-09-19	criteria provided, single submitter	clinical testing	The c.1845G>A variant (also known as p.E615E), located in coding exon 12 of the LDLR gene, results from a G to A substitution at nucleotide position 1845. This nucleotide substitution does not change the amino acid at codon 615. However, this change occurs in the last base pair of coding exon 12, which makes it likely to have some effect on normal mRNA splicing. This alteration was detected in an individual with possible familial hypercholesterolaemia (Taylor A et al. Clin. Genet., 2007 Jun;71:561-8). Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice donor site; however, direct evidence is unavailable. This amino acid position is highly conserved in available vertebrate species. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV003235161	SCV003932925	likely pathogenic	not provided	2022-12-16	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Alters the last nucleotide of the exon and is predicted to destroy the splice donor site and result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown; This variant is associated with the following publications: (PMID: 17539906, 34037665, 32220565)