Submissions for variant NM_000527.5(LDLR):c.91G>A (p.Glu31Lys)

gnomAD frequency: 0.00001  dbSNP: rs776421777

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000237765	SCV000294459	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Color Diagnostics, LLC DBA Color Health	RCV000775021	SCV000909118	uncertain significance	Familial hypercholesterolemia	2023-03-01	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Glu10Lys in the mature protein) replaces glutamic acid with lysine at codon 31 of the LDLR protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in three individuals affected with familial hypercholesterolemia (PMID: 20145306, 32044282; Color internal data). This variant has been identified in 7/282432 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	RCV000775021	SCV001211234	uncertain significance	Familial hypercholesterolemia	2021-09-01	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid with lysine at codon 31 of the LDLR protein (p.Glu31Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs776421777, ExAC 0.002%). This missense change has been observed in individual(s) with clinical features of familial hypercholesterolemia (PMID: 20145306). ClinVar contains an entry for this variant (Variation ID: 251013). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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.
Centogene AG - the Rare Disease Company	RCV000237765	SCV002028301	uncertain significance	Hypercholesterolemia, familial, 1	2021-08-26	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002307470	SCV002600527	uncertain significance	not specified	2022-10-16	criteria provided, single submitter	clinical testing	Variant summary: LDLR c.91G>A (p.Glu31Lys) results in a conservative amino acid change located in the Low-density lipoprotein (LDL) receptor class A repeat (IPR002172) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251034 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.91G>A has been reported in the literature in individuals affected with Familial Hypercholesterolemia (e.g. Chmara_2010, Kusters_2013, Setia_2020, Elfatih_2021). These reports do not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters have assessed the variant since 2014: four classified the variant as uncertain significance and one as likely pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance.
All of Us Research Program, National Institutes of Health	RCV000237765	SCV004820113	uncertain significance	Hypercholesterolemia, familial, 1	2023-11-28	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Glu10Lys in the mature protein) replaces glutamic acid with lysine at codon 31 of the LDLR protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in three individuals affected with familial hypercholesterolemia (PMID: 20145306, 32044282; Color internal data). This variant has been identified in 7/282432 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.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000237765	SCV000606012	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research
Natera, Inc.	RCV000775021	SCV002086358	uncertain significance	Familial hypercholesterolemia	2021-03-14	no assertion criteria provided	clinical testing