Submissions for variant NM_000527.5(LDLR):c.2029T>C (p.Cys677Arg)

gnomAD frequency: 0.00001  dbSNP: rs775092314

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000211671	SCV000295824	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Robarts Research Institute, Western University	RCV000211671	SCV000484752	likely pathogenic	Hypercholesterolemia, familial, 1		criteria provided, single submitter	clinical testing
Invitae	RCV000791370	SCV000830362	pathogenic	Familial hypercholesterolemia	2023-12-13	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 677 of the LDLR protein (p.Cys677Arg). This variant is present in population databases (rs775092314, gnomAD 0.0009%). This missense change has been observed in individuals with hypercholesterolemia (PMID: 1301956, 10208479, 17142622, 19487412, 22883975, 27680772, 27765764). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Cys656Arg. ClinVar contains an entry for this variant (Variation ID: 226384). 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%. This variant disrupts the p.Cys677 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 9763532, 16389549, 28235710), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000211671	SCV000839986	likely pathogenic	Hypercholesterolemia, familial, 1	2018-04-13	criteria provided, single submitter	clinical testing	This c.2029T>C (p.Cys677Arg) variant in the LDLR gene has been reported in multiple individuals with familial hypercholesterolemia (PMID: 1301956, 10208479, 10559517) or myocardial infarction (PMID 25487149). Functional studies have indicated that the p.Cys677Arg variant in the LDLR protein has 5-15% receptor activity compared to wild-type LDLR protein (PMID: 1301956). The c.2029T>C variant is rare in the general population and cysteine at position 677 of the LDLR protein is highly evolutionarily conserved. The c.2029T>C (p.Cys677Arg) variant in the LDLR gene is classified as likely pathogenic.
GeneDx	RCV001843494	SCV002102633	pathogenic	not provided	2022-02-18	criteria provided, single submitter	clinical testing	Also known as FH New York-1 and p.C656R; Located within the LDL-receptor EGF precursor domain 3, and participates in disulfide bonding with another cysteine residue which is critical for correct protein structure (Sudhof et al., 1985; Rudenko et al., 2002); Not observed at significant frequency in large population cohorts (gnomAD); 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: 10559517, 25487149, 1301956, 16389549, 17142622, 22883975, 27680772, 27765764, 31447099, 32041611, 34037665, 33087929, 2988123, 12459547, 10208479, 19487412)
AiLife Diagnostics, AiLife Diagnostics	RCV001843494	SCV002502712	likely pathogenic	not provided	2021-08-17	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002415889	SCV002718691	pathogenic	Cardiovascular phenotype	2021-12-15	criteria provided, single submitter	clinical testing	The p.C677R pathogenic mutation (also known as c.2029T>C), located in coding exon 14 of the LDLR gene, results from a T to C substitution at nucleotide position 2029. The cysteine at codon 677 is replaced by arginine, an amino acid with highly dissimilar properties. This alteration was detected in conjunction with another alteration in the LDLR gene in an individual whose protein activity was 5-15% of normal (Hobbs HH et al. Hum Mutat. 1992;1(6):445-66). Subsequent studies observed this alteration in several individuals diagnosed with familial hypercholesterolemia (FH) (Humphries SE et al. J Mol Med. 2006; 84(3):203-14; Tosi I et al. Atherosclerosis. 2007;194(1):102-11). In a case report, this alteration was described to co-segregate with FH in multiple individuals in one family (Bima AI et al. Ann Clin Biochem. 2009;46(Pt 5):420-2). Another alteration affecting the same codon (p.C677Y c.2030G>A) has also been described in patients with FH (Salazar LA et al. Hum Mutat. 2002;19(4):462-3). Based on the supporting evidence, p.C677R is interpreted as a disease-causing mutation.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV004017508	SCV004847793	likely pathogenic	Homozygous familial hypercholesterolemia	2019-10-11	criteria provided, single submitter	clinical testing	The p.Cys677Arg variant in LDLR has been reported in at least 7 individuals with hypercholesterolemia and segregated with disease in 6 affected individuals from 1 family (Hobbs 1992, Heath 1999, Humphries 2006, Bima 2009, Hooper 2012, Martin 2016, Wang 2016). It has also been identified in 1/113610 of European chromosomes by gnomAD (http://gnomad.broadinstitute.org) and has been reported in ClinVar (Variation ID 226384). An in vitro functional study and computational prediction tools support an impact on protein function (Hobbs 1992). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant familial . ACMG/AMP Criteria applied: PM2, PS4_Moderate, PP1_Moderate, PP3, PS3_Supporting.
Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	RCV000211671	SCV000268653	pathogenic	Hypercholesterolemia, familial, 1	2008-06-05	no assertion criteria provided	clinical testing