Submissions for variant NM_000527.5(LDLR):c.502G>C (p.Asp168His)

dbSNP: rs200727689

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000238302	SCV000294747	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	RCV000238302	SCV000322900	pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research	0/190 non-FH alleles
Labcorp Genetics (formerly Invitae), Labcorp	RCV001071431	SCV001236737	pathogenic	Familial hypercholesterolemia	2022-11-24	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 168 of the LDLR protein (p.Asp168His). Experimental studies have shown that this missense change affects LDLR function (PMID: 8462973). This variant disrupts the p.Asp168 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9259195, 9678702, 12124988, 15556094, 16205024, 19007590). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. 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: 251258). This variant is also known as p.D147H and FH-Sephardic. This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 8462973, 16250003, 20828696, 28104544). It has also been observed to segregate with disease in related individuals.
Ambry Genetics	RCV002338782	SCV002642996	pathogenic	Cardiovascular phenotype	2020-10-05	criteria provided, single submitter	clinical testing	The p.D168H pathogenic mutation (also known as c.502G>C), located in coding exon 4 of the LDLR gene, results from a G to C substitution at nucleotide position 502. The aspartic acid at codon 168 is replaced by histidine, an amino acid with similar properties. This mutation was first reported (as legacy p.D147H) in multiple families from a Sephardic Jewish hypercholesterolemia cohort, including one family with segregation in multiple affected heterozygous and homozygous cases; in vitro functional studies in homozygous fibroblasts demonstrated significant impact on LDLR trafficking and LDL binding (Leitersdorf E et al. Hum. Genet., 1993 Mar;91:141-7). This mutation has also been reported in additional familial hypercholesterolemia (FH) cohorts (Fouchier SW et al. Hum. Mutat., 2005 Dec;26:550-6; Medeiros AM et al. Atherosclerosis, 2010 Oct;212:553-8; Durst R et al. Atherosclerosis, 2017 02;257:55-63). In addition, alternate amino acid substitutions at this codon, p.D168Y, p.D168N, p.D168A, p.D168E, p.D168G, have also been reported in individuals with FH, indicating this position may be a hotspot location (Christiano AM et al. Am. J. Hum. Genet., 1996 Apr;58:671-81; Day IN et al. Hum. Mutat., 1997;10:116-27; Santos PC et al. Atherosclerosis, 2014 Mar;233:206-10; Sözen MM et al. Atherosclerosis, 2005 May;180:63-71; Chmara M et al. J. Appl. Genet., 2010;51:95-106). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV004999167	SCV005625849	pathogenic	not provided	2024-02-29	criteria provided, single submitter	clinical testing	The LDLR c.502G>C (p.Asp168His) variant, also known as FH Sephardic, has been reported in the published literature in individuals and families with familial hypercholesterolemia (FH) (PMIDs: 8462973 (1993), 8882879 (1996), 16250003 (2005), 20828696 (2010), 28104544 (2017), 33418990 (2021)), as well as being described as a founder variant for FH within the Sephardic Jewish population (PMIDs: 8462973 (1993), 8882879 (1996)). This variant has shown to segregate with disease in one Sephardic Jewish family (PMID: 8462973 (1993)). Functional studies show this variant decreases normal LDL receptor transportation activity and antibody binding (PMID: 8462973 (1993)) in addition to impacting hydrogen bonding and amino acid residue acidity (PMID: 31401775 (2019)). Other variants impacting the p.168 residue have been seen in individuals with FH and are classified as pathogenic (PMIDs: 9259195 (1997), 9678702 (1998), 12124988 (2002), 15556094 (2004), 16205024 (2005), 15823276 (2005), 19007590 (2008), 20145306 (2008), 24529145 (2014)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000238302	SCV000606138	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research