Submissions for variant NM_000527.5(LDLR):c.1846-10G>T

gnomAD frequency: 0.00006  dbSNP: rs368243304

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000237306	SCV004022445	likely benign	Hypercholesterolemia, familial, 1	2023-04-28	reviewed by expert panel	curation	NM_000527.5(LDLR):c.1846-10G>T variant is classified as Likely benign for Familial Hypercholesterolemia by applying evidence codes (PM2, BP2 and BP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PM2 - PopMax MAF = 0.00009643 (0.0096%) in Ashkenazi Jewish exomes+genomes (gnomAD v2.1.1). BP2 - Variant identified in an index case with heterozygous FH phenotype (LDLc = 6.5 mmol/l) and APOB variant p.(Arg3527Gln), classified as Pathogenic by the general ACMG guidelines from Robarts Research Institute. BP4 - No REVEL available, splicing evaluation needed. Functional data on splicing not available. A) variant is located at -20 to +3 bases of canonical acceptor splicing site MES scores: de novo acceptor = 11.36, authentic acceptor = 9.58. Ratio variant/wt = 1.18. It is above 1.0. B) The variant is located within range but does not create de novo GT site. C) Variant not on limits. Variant is not predicted to alter splicing. So BP4 is met. Variant has 2 BP evidence codes towards Benign, enough to classify as Likely benign, and only 1 PM evidence code towards Pathogenic. The Benign criteria overwhelms the Pathogenic criteria, so we are confident in classifying this variant as Likely benign.
LDLR-LOVD, British Heart Foundation	RCV000237306	SCV000295704	likely benign	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Robarts Research Institute, Western University	RCV000237306	SCV000484791	uncertain significance	Hypercholesterolemia, familial, 1	2019-08-22	criteria provided, single submitter	clinical testing
GeneDx	RCV000599958	SCV000722314	likely benign	not specified	2017-08-29	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000599958	SCV000919574	uncertain significance	not specified	2017-11-14	criteria provided, single submitter	clinical testing	Variant summary: The LDLR c.1846-10G>T variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a benign outcome for this variant. In Alamut 3/5 splice prediction tools predict significant enhancement effect on the exon 13 acceptor site. In a published study also a slight increase in affinity was predicted for the splicing acceptor site using a different set of in silico tools (Usifo 2012). ESE finder predicts that this variant may affect the binding sites of the splicing factors SRp55, ASF/SF2 and SC35. Another study, using other in silico algorithms for splicing analyses, predicted also a deleterious score for the variant (Wang 2016). These predictions however have not been confirmed by functional studies. This variant was found in 12/277244 control chromosomes at a frequency of 0.0000433, which does not exceed the estimated maximal expected allele frequency of a pathogenic LDLR variant (0.0012508). The variant of interest has been reported in affected individuals (Usifo 2012, Wang 2016), where one of the patients also carried a pathogenic APOB variant c.10580G>A (p.Arg3527Gln), suggesting a possibly non-pathogenic role of variant of interest. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Invitae	RCV000869000	SCV001010389	likely benign	Familial hypercholesterolemia	2024-01-22	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000869000	SCV001339284	likely benign	Familial hypercholesterolemia	2017-07-06	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000237306	SCV001422916	likely benign	Hypercholesterolemia, familial, 1	2020-01-22	criteria provided, single submitter	curation	The c.1846-10G>T variant in LDLR has been reported in at least 1 individual with Familial Hypercholesterolemia in ClinVar (Variation ID: 252072), and has been identified in 0.004595% (13/282890) of chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs368243304). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported likely benign and likely pathogenic in ClinVar (Variation ID: 252072). Computational prediction tools and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely benign. ACMG/AMP Criteria applied: BP4, BP7 (Richards 2015).
All of Us Research Program, National Institutes of Health	RCV000237306	SCV004821025	likely benign	Hypercholesterolemia, familial, 1	2023-12-13	criteria provided, single submitter	clinical testing