Submissions for variant NM_000527.5(LDLR):c.1016T>C (p.Leu339Pro)

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000237676	SCV000295140	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Laboratory of Genetics and Molecular Cardiology, University of São Paulo	RCV000237676	SCV000588539	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001797694	SCV002041587	pathogenic	Familial hypercholesterolemia	2021-11-29	criteria provided, single submitter	clinical testing	Variant summary: LDLR c.1016T>C (p.Leu339Pro) results in a non-conservative amino acid change located in the EGF like Domain (IPR000742) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251028 control chromosomes (gnomAD). c.1016T>C has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia and was reported to segregate with disease in affected family members (Chiou_2010 & 2017, Chan_2018, Huang_2021). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV001797694	SCV002289111	pathogenic	Familial hypercholesterolemia	2023-07-07	criteria provided, single submitter	clinical testing	This variant is also known as p.P318L. This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 339 of the LDLR protein (p.Leu339Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 20538126, 30592178; Invitae). ClinVar contains an entry for this variant (Variation ID: 251597). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function. For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV002261021	SCV002541497	uncertain significance	not provided	2022-02-18	criteria provided, single submitter	clinical testing	PP1_moderate, PM2_supporting, PS4_moderate
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV002261021	SCV004219931	pathogenic	not provided	2023-02-07	criteria provided, single submitter	clinical testing	This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in multiple individuals affected with familial hypercholesterolemia (FH) (PMID: 20538126 (2010), 21376320 (2011), 28502495 (2017), 30592178 (2019), 30592178 (2021)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic.
Ambry Genetics	RCV004020957	SCV004897963	likely pathogenic	Cardiovascular phenotype	2024-01-08	criteria provided, single submitter	clinical testing	The c.1016T>C (p.L339P) alteration is located in exon 7 (coding exon 7) of the LDLR gene. This alteration results from a T to C substitution at nucleotide position 1016, causing the leucine (L) at amino acid position 339 to be replaced by a proline (P). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration, which is also reported as p.L318P, has been detected in individuals with familial hypercholesterolemia (FH), specifically of East Asian ancestry (Chiou, 2010; Chan, 2019). Additionally, this alteration was detected as compound heterozygous with additional alterations in LDLR in individuals with concerns for homozygous FH (Du, 2022). This amino acid position is not well conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic.