Submissions for variant NM_000527.5(LDLR):c.2375T>C (p.Ile792Thr)

gnomAD frequency: 0.00003  dbSNP: rs764493597

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000238445	SCV002817152	uncertain significance	Hypercholesterolemia, familial, 1	2022-08-26	reviewed by expert panel	curation	The NM_000527.5 (LDLR):c.2375T>C (p. Ile792Thr) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PP3) 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: PP3: REVEL = 0.773. PM2 not met: PopMax MAF = 0.00056 in Latino population in gnomAD (gnomAD version: 2.1.1). PP4, PS4 not applicable: Variant did not meet PM2. PS3 not met: Functional data is not available. PM5 not met: There is one other variant in the same codon: LDLR: NM_000527:c.2374A>T (p.Ile792Phe) is classified as Uncertain significance - insufficient evidence by these guidelines. Therefore PM5 is not met.
LDLR-LOVD, British Heart Foundation	RCV000238445	SCV000295964	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Fundacion Hipercolesterolemia Familiar	RCV000238445	SCV000607695	uncertain significance	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Color Diagnostics, LLC DBA Color Health	RCV001523921	SCV001733661	uncertain significance	Familial hypercholesterolemia	2023-05-03	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Ile771Thr in the mature protein) replaces isoleucine with threonine at codon 792 of the LDLR protein. Computational prediction suggests that this variant may have a 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 individuals affected with familial hypercholesterolemia (PMID: 19318025, 19446849, 23375686). This variant has been identified in 29/282798 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.
GeneDx	RCV001558972	SCV001781020	uncertain significance	not provided	2020-05-04	criteria provided, single submitter	clinical testing	Reported in association with familial hypercholesterolemia (Guardamagna et al., 2009; Alonso et al., 2009); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32719484, 19318025, 19446849, 23375686)
AiLife Diagnostics, AiLife Diagnostics	RCV001558972	SCV002502948	uncertain significance	not provided	2021-11-05	criteria provided, single submitter	clinical testing
Mendelics	RCV002247687	SCV002518185	uncertain significance	not specified	2022-05-04	criteria provided, single submitter	clinical testing
New York Genome Center	RCV000238445	SCV002764284	uncertain significance	Hypercholesterolemia, familial, 1	2021-06-04	criteria provided, single submitter	clinical testing	The c.2375T>C (p.Ile792Thr) variant identified in the LDLR gene substitutes a well conserved Isoleucine for Threonine at amino acid 792/861 (exon 16/18). This variant is found with low frequency in gnomAD(v2.1.1)(29 heterozygotes, 0 homozygotes; allele frequency: 1.03e-4), suggesting it is not a common benign variant in the populations represented in that database. In silico algorithms predict this variant to be Damaging (SIFT; score:0.024) and Pathogenic (REVEL; score:0.773) to the function of the canonical transcript. This variant is reported in ClinVar as both a Variant of Uncertain Significance as well as Likely Pathogenic (VarID:252295), and has been reported in individuals with hypercholesterolemia [PMID:19446849, 18096825, 19318025, 23375686], and has also been identified in healthy unaffected individuals [PMID:32719484]. The c.2375T>C (p.Ile792Thr) variant identified in the LDLR gene is reported as a Variant of UncertainSignificance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001523921	SCV003269197	uncertain significance	Familial hypercholesterolemia	2024-01-12	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 792 of the LDLR protein (p.Ile792Thr). This variant is present in population databases (rs764493597, gnomAD 0.06%). This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 18096825, 19446849, 23375686, 34456049, 35913489). ClinVar contains an entry for this variant (Variation ID: 252295). 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 with a positive predictive value of 95%. 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.
Revvity Omics, Revvity	RCV000238445	SCV003816532	uncertain significance	Hypercholesterolemia, familial, 1	2021-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003372668	SCV004087580	uncertain significance	Cardiovascular phenotype	2023-07-20	criteria provided, single submitter	clinical testing	The p.I792T variant (also known as c.2375T>C), located in coding exon 16 of the LDLR gene, results from a T to C substitution at nucleotide position 2375. The isoleucine at codon 792 is replaced by threonine, an amino acid with similar properties. This alteration has been reported in familial hypercholesterolemia (FH) cohorts; however, clinical details were limited (Guardamagna O et al. J Pediatr, 2009 Aug;155:199-204.e2; Junyent M et al. Arterioscler Thromb Vasc Biol, 2008 Mar;28:580-6; Alonso R et al. Clin Biochem, 2009 Jun;42:899-903; Bertolini S et al. Atherosclerosis, 2013 Apr;227:342-8; Sánchez-Hernández RM et al. Circ Cardiovasc Genet, 2016 Dec;9:504-510). 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.
All of Us Research Program, National Institutes of Health	RCV000238445	SCV004820676	uncertain significance	Hypercholesterolemia, familial, 1	2024-01-08	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Ile771Thr in the mature protein) replaces isoleucine with threonine at codon 792 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 individuals affected with familial hypercholesterolemia (PMID: 19318025, 19446849, 23375686), as well as in healthy individuals (PMID: 32719484). This variant has been identified in 29/282798 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.
Natera, Inc.	RCV001523921	SCV002086876	uncertain significance	Familial hypercholesterolemia	2020-01-14	no assertion criteria provided	clinical testing