Submissions for variant NM_000527.5(LDLR):c.1078G>C (p.Asp360His)

gnomAD frequency: 0.00004  dbSNP: rs777926251

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000627169	SCV005688674	uncertain significance	Hypercholesterolemia, familial, 1	2024-10-28	reviewed by expert panel	curation	The NM_000527.5(LDLR):c.1078G>C (p.Asp360His) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying no ACMG/AMP evidence codes as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 28 October 2024.
Iberoamerican FH Network	RCV000627169	SCV000748048	uncertain significance	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Color Diagnostics, LLC DBA Color Health	RCV000775610	SCV000909974	uncertain significance	Familial hypercholesterolemia	2023-02-01	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Asp339His in the mature protein) replaces aspartic acid with histidine at codon 360 of the LDLR protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in over twenty heterozygous Hispanic individuals affected with hypercholesterolemia (PMID: 23064986, 29576406, 32113782) and in a homozygous individual affected with severe hypercholesterolemia and xanthoma (PMID: 29576406). However, this variant is common in the general population and has been identified in 43/282710 chromosomes (40/35438 Latino chromosomes; 0.1128%) by the Genome Aggregation Database (gnomAD). A study conducted in a Mexican population has reported that carriers of this variant show significantly higher LDL-C levels than non-carriers (PMID: 32113782). This study only looked for the presence of this variant in affected individuals and did not screen for other variants in the LDLR gene or other genes known to cause familial hypercholesterolemia. Therefore, it is not clear if this variant is responsible for the observed phenotype. 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	RCV000775610	SCV001010068	likely benign	Familial hypercholesterolemia	2024-12-17	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000627169	SCV001286366	uncertain significance	Hypercholesterolemia, familial, 1	2019-04-18	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001199891	SCV001370646	uncertain significance	not specified	2024-11-19	criteria provided, single submitter	clinical testing	Variant summary: LDLR c.1078G>C (p.Asp360His) results in a non-conservative amino acid change located in the EGF-like calcium-binding domain (IPR001881) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00016 in 251310 control chromosomes, predominantly at a frequency of 0.0011 within the Latino subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within Latino control individuals in the gnomAD database is approximately equal to the estimated maximal expected allele frequency for a pathogenic variant in LDLR causing Early Onset Coronary Artery Disease phenotype (0.001). c.1078G>C has been reported in the literature in individuals affected with hypercholesterolemia, including in a family with 1 homozygous and 4 heterozygous affected individuals (e.g., Ahmad_2012, Vasquez-Cardenas_2016 (no PMID), Hernandez-Flores_2018, Hernandez-Flores_2020). Additionally, one study suggested the variant may represent a founder mutation in an isolated Mexican community, however this could not be conclusively confirmed as the study only utilized targeted genotyping (e.g., Hernandez-Flores_2020). These reports therefore do not provide unequivocal conclusions about association of the variant with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 23064986, 32113782, 29576406). ClinVar contains an entry for this variant (Variation ID: 523715). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Centogene AG - the Rare Disease Company	RCV000627169	SCV002059222	uncertain significance	Hypercholesterolemia, familial, 1	2020-09-04	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002420657	SCV002727768	likely benign	Cardiovascular phenotype	2024-07-03	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
All of Us Research Program, National Institutes of Health	RCV000627169	SCV004820263	uncertain significance	Hypercholesterolemia, familial, 1	2024-09-23	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Asp339His in the mature protein) replaces aspartic acid with histidine at codon 360 of the LDLR protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in over twenty heterozygous Hispanic individuals affected with hypercholesterolemia (PMID: 23064986, 29576406, 32113782) and in a homozygous individual affected with severe hypercholesterolemia and xanthoma (PMID: 29576406). However, this variant is common in the general population and has been identified in 43/282710 chromosomes (40/35438 Latino chromosomes; 0.1128%) by the Genome Aggregation Database (gnomAD). A study conducted in a Mexican population has reported that carriers of this variant show significantly higher LDL-C levels than non-carriers (PMID: 32113782). This study only looked for the presence of this variant in affected individuals and did not screen for other variants in the LDLR gene or other genes known to cause familial hypercholesterolemia. Therefore, it is not clear if this variant is responsible for the observed phenotype. 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.