Submissions for variant NM_000527.5(LDLR):c.2251C>T (p.Arg751Trp)

gnomAD frequency: 0.00005  dbSNP: rs756864388

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV002279968	SCV002568109	likely benign	Hypercholesterolemia, familial, 1	2022-05-26	reviewed by expert panel	curation	NM_000527.5(LDLR): c.2251C>T (p.Arg751Trp) variant is classified as Likely benign for Familial Hypercholesterolemia by applying evidence codes PM2, BS2 and BP4 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 - PopMax MAF = 0.0001202 (0.01202%) in African/African American exomes+genomes (gnomAD v2.1.1). BP4 - REVEL = 0.428, it is below 0.50, splicing evaluation required. Variant is exonic and at least 50bp downstream from canonical donor site, but it does not create AG/GT. BS2 - Variant identified in 717 heterozygotes and 72 homozygotes (PMID: 25414273). These subjects had the same level of LDLc as non-carriers (N=2408).
Color Diagnostics, LLC DBA Color Health	RCV001188886	SCV001356058	likely benign	Familial hypercholesterolemia	2021-03-12	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193792	SCV001362903	likely benign	not specified	2019-11-25	criteria provided, single submitter	clinical testing	Variant summary: LDLR c.2251C>T (p.Arg751Trp) 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. The variant allele was found at a frequency of 1.6e-05 in 251320 control chromosomes in gnomAD. c.2251C>T has been reported in the literature in Inuit individuals with high LDL cholesterol but it was also detected at a frequency of 0.14 in Inuit populations from Alaska, Canada and Greenland (Dube_2015). This variant frequency is approximately 108-fold of the estimated maximal expected allele frequency for a pathogenic variant in LDLR causing Familial Hypercholesterolemia phenotype (0.0013), suggesting that the variant is a benign polymorphism prevalent in populations of Inuit origin. However, given Inuit may be regarded as an isolated population it cannot be excluded that the variant could still be clinically relevant. Following in vitro functional assessment p.R751W was determined to have reduced mean mature LDLR expression and a non-significant reduction in binding ability (Dube_2015). In addition, authors stratified plasma lipoprotein profiles based on p.R751W genotype and showed that the variant was not significantly associated with LDL cholesterol overall. They concluded that the variant was not associated with increased risk of clinically actionable hypercholesterolemia. Co-occurrence with a pathogenic variant has been reported (LDLR c.409G>A, p.Gly137Ser; Internal testing). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001812241	SCV001474195	likely benign	not provided	2020-04-30	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001188886	SCV001727547	benign	Familial hypercholesterolemia	2023-11-27	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004033388	SCV004897969	likely benign	Cardiovascular phenotype	2023-10-30	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.