Submissions for variant NM_000527.5(LDLR):c.2411T>C (p.Leu804Pro)

gnomAD frequency: 0.00003  dbSNP: rs879255203

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000238240	SCV000295998	uncertain significance	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Color Diagnostics, LLC DBA Color Health	RCV001182070	SCV001347394	uncertain significance	Familial hypercholesterolemia	2019-07-30	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Leu783Pro in the mature protein) replaces leucine with proline at codon 804 of the LDLR protein. Computational prediction tools and conservation analyses suggest that this variant may not impact protein function. Of note, leucine at this position is poorly conserved in mammals, suggesting that other amino acids may be tolerated for function. Computational splicing tools suggest that this variant may not impact RNA splicing. A functional study has shown that this variant may partially affect integration of the LDLR protein in the cell membrane (PMID: 26220972). However, clinical relevance of this observation is not known. This variant has been reported in an individual affected with familial hypercholesterolemia (PMID: 16250003). This variant has been identified in 1/31392 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001582802	SCV001821225	uncertain significance	not specified	2021-08-12	criteria provided, single submitter	clinical testing	Variant summary: LDLR c.2411T>C (p.Leu804Pro) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251326 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2411T>C has been reported in the literature in an individual affected with Familial Hypercholesterolemia (Fouchier_2005). This report does not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. One functional study has reported the variant to cause defective gamma-secretase cleavage, but otherwise appears to be similar to the WT-LDLR. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Fulgent Genetics, Fulgent Genetics	RCV000238240	SCV002791786	uncertain significance	Hypercholesterolemia, familial, 1	2021-09-09	criteria provided, single submitter	clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000238240	SCV000606646	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research
Natera, Inc.	RCV001182070	SCV002086879	uncertain significance	Familial hypercholesterolemia	2020-02-20	no assertion criteria provided	clinical testing