Submissions for variant NM_000527.5(LDLR):c.932A>G (p.Lys311Arg)

dbSNP: rs761765254

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000238436	SCV002506362	uncertain significance	Hypercholesterolemia, familial, 1	2022-01-17	reviewed by expert panel	curation	The NM_000527.5(LDLR):c.932A>G (p.Lys311Arg) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PM3 and PP4) 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 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is Met. PM3 - Variant meets PM2 and is identified in an index case with homozygous FH phenotype (plasma cholesterol > 600mg/dL) and LDLR variant NM_000527.5(LDLR):c.910G>T (p.Asp304Tyr) (ClinVar ID: 251517), classified as Likely pathogenic by these guidelines, in trans (PMID: 1301940), so PM3 is Met. PP4 - Variant meets PM2 and is identified in 1 index-case with SB/DLCN score of definite FH (plasma cholesterol > 600mg/dL with tendon xanthomas) from France (PMID: 1301940), so PP4 is Met.
LDLR-LOVD, British Heart Foundation	RCV000238436	SCV000295064	likely benign	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	RCV000238436	SCV000503256	likely pathogenic	Hypercholesterolemia, familial, 1	2016-12-16	criteria provided, single submitter	clinical testing	subjects mutated among 2600 FH index cases screened = 3 , family members = 2 with co-segregation c.932A>G, c.939C>G / p.Lys311Arg, p.Cys313Trp systematicaly associated (Van Leuven et al. Atherosclerosis 2001) / Software predictions: Conflicting
Labcorp Genetics (formerly Invitae), Labcorp	RCV000791455	SCV000830603	uncertain significance	Familial hypercholesterolemia	2024-05-05	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 311 of the LDLR protein (p.Lys311Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypercholesterolemia (PMID: 1301940, 11810272, 15523646, 20506408, 32331935). This variant is also known as K290R. ClinVar contains an entry for this variant (Variation ID: 251532). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on LDLR protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color Diagnostics, LLC DBA Color Health	RCV000791455	SCV001349542	uncertain significance	Familial hypercholesterolemia	2019-05-30	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Lys290Arg in the mature protein) replaces lysine with arginine at codon 311 of the LDLR protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in individuals affected with hypercholesterolemia (PMID: 1301940, 15523646, 20506408). This variant has not been identified 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.
Ambry Genetics	RCV002374400	SCV002684865	uncertain significance	Cardiovascular phenotype	2022-06-27	criteria provided, single submitter	clinical testing	The p.K311R variant (also known as c.932A>G), located in coding exon 6 of the LDLR gene, results from an A to G substitution at nucleotide position 932. The lysine at codon 311 is replaced by arginine, an amino acid with highly similar properties. This variant (also referred to as K290R) has been detected in individuals reported to have FH or from FH cohorts, and has been detected with the LDLR p.C313W variant (Descamps OS et al. Atherosclerosis, 2001 Aug;157:514-8; Fouchier SW et al. Hum Genet, 2001 Dec;109:602-15; Van Leuven F et al. Atherosclerosis. 2001 Feb;154(3):567-77; Amsellem S et al. Hum Genet, 2002 Dec;111:501-10; van der Graaf A et al. Circulation, 2011 Mar;123:1167-73Tada H et al. J Clin Lipidol Mar;14:346-351.e9). This variant co-occurred in trans with another variant in the LDLR gene in an individual with clinical homozygous FH presentation (Loux N et al. Hum Mutat, 1992;1:325-32). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000238436	SCV000606272	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research