Submissions for variant NM_000527.5(LDLR):c.1366C>T (p.Leu456Phe)

dbSNP: rs761004553

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV004765348	SCV005375281	uncertain significance	Hypercholesterolemia, familial, 1	2023-06-23	reviewed by expert panel	curation	The NM_000527.5 (LDLR):c. 1366C>T (p. Leu456Phe) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2 and BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 June 2023. The supporting evidence is as follows: PM2: PopMax MAF=0.00003 in South Asian population in gnomAD (gnomAD v2.1.1). BP4: REVEL=0.487, it is not above 0.75, splicing evaluation required. Functional data on splicing is not available. MES performed: A) Variant is not on limits. B) Variant is on limit but does not crate de novo AG. Variant created GT however is not on limit. C) Variant is on limit and nearby three intra-exonic AGs: cctcctgcctcagcacccAGc/ttt , Var/Wt cryptic score = 0.37/-0.2 = -0.15, it is <1.1; ctcagcacccagc/tttgacAGagc, Var/Wt cryptic score = -3.2/-2.9 = 1.103, it is = 1.1, however both scores are negative; and agcacccagc/tttgacagAGccc, Var/Wt cryptic score = -33.4/-34.48 = 0.97, it is <1.1. MES score for canonical intron 9 acceptor cttctctcctcctgcctcAGcac is 6.76, so none of the Var cryptic scores/Wt score is >0.9. Variant is not predicted to alter splicing and REVEL score is below 0.5, therefore BP4 is met.
Color Diagnostics, LLC DBA Color Health	RCV001189133	SCV001356345	uncertain significance	Familial hypercholesterolemia	2019-09-23	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Leu435Phe in the mature protein) replaces leucine with phenylalanine at codon 456 of the LDLR protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold ≤0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with familial hypercholesterolemia in the literature. This variant has been identified in 1/250830 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001189133	SCV004612387	likely pathogenic	Familial hypercholesterolemia	2023-05-14	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Leu456 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19026292, 23064986). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 926526). This variant has not been reported in the literature in individuals affected with LDLR-related conditions. This variant is present in population databases (rs761004553, gnomAD 0.003%). This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 456 of the LDLR protein (p.Leu456Phe).