Submissions for variant NM_000527.5(LDLR):c.1012T>G (p.Cys338Gly)

dbSNP: rs879254753

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000237730	SCV000295137	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589507	SCV000697179	likely pathogenic	Familial hypercholesterolemia	2016-11-02	criteria provided, single submitter	clinical testing	Variant summary: The LDLR c.1012T>G (p.Cys338Gly) variant, alternatively also known as C317G, involves the alteration of a conserved nucleotide and is located in the epidermal growth factor (EGR) precursor homology domain of the protein. 5/5 in silico tools predict a damaging outcome for this variant. This variant is absent in 120874 control chromosomes. The variant has been reported in at least four FH patients in literature including a family where the variant was said to co-segregate with disease (Lombardi_2000, Fard-Esfahani_2005, Donato_2014). This variant is expected to be deleterious as mutations involving Cys residues in this gene are recurrent and may affect folding of the protein (Lombardi_2000, Donato_2014). In addition, multiple reports of variation at LDLR residue p.Cys338 have been reported in FH patients including missense changes of this residue to glycine (Gly), serine (Ser), arginine (Arg), and tyrosine (Tyr), as well as a nonsense change (p.Cys338X), suggesting a notion that this residue is mutational hot-spot. Functional studies have shown that binding, uptake, and degradation of iodinated LDL in skin fibroblasts from a patient homozygous for p.Cys338Tyr variant was <10% of normal (reviewed by Donato_2014). Furthermore, one research institution in ClinVar has classified the variant as likely pathogenic. Taken together, this variant is currently classified as likely pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000589507	SCV000909151	likely pathogenic	Familial hypercholesterolemia	2019-03-22	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Cys317Gly in the mature protein) is located in the EGF-like repeat A of the EGF precursor homology domain of the LDLR protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. Although functional assays have not been performed, this variant changes one of the functionally critical cysteine residues that form intra-repeat disulfide bonds in the EGF precursor homology domain (PMID: 3495735, 4750422) and is expected to have deleterious impact on the LDLR protein folding and stability. This variant has been reported in two Dutch individuals with hypercholesterolemia (PMID: 10735632, 21382890) and in a dyslipidemic patient undergoing LDL apheresis (PMID: 24420163). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Different missense variants at the same position (Cys338Ser, Cys338Arg, Cys338Tyr) have been reported in individuals affected with familial hypercholesterolemia. Based on available evidence, this variant is classified as Likely Pathogenic.
Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia	RCV000237730	SCV001432586	pathogenic	Hypercholesterolemia, familial, 1	2019-05-11	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV000589507	SCV002309343	pathogenic	Familial hypercholesterolemia	2025-01-13	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 338 of the LDLR protein (p.Cys338Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of familial hypercholesterolemia (PMID: 10735632, 15885240, 24420163, 31345425). Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this LDLR variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 363,995 individuals referred to our laboratory for LDLR testing. This variant is also known as C317G. ClinVar contains an entry for this variant (Variation ID: 251594). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt LDLR protein function with a positive predictive value of 95%. This variant affects a cysteine residue located within an LDLRA or epidermal-growth-factor (EGF)-like domains of the LDLR protein. Cysteine residues in these domains have been shown to be involved in the formation of disulfide bridges, which are critical for protein structure and stability (PMID: 7548065, 7603991, 7979249). In addition, missense substitutions within the LDLRA and EGF-like domains affecting cysteine residues are overrepresented among patients with hypercholesterolemia (PMID: 18325082). This variant disrupts the p.Cys338 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 8568489, 10735632, 10924730, 24420163), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002365244	SCV002625797	pathogenic	Cardiovascular phenotype	2019-05-22	criteria provided, single submitter	clinical testing	The p.C338G pathogenic mutation (also known as c.1012T>G), located in coding exon 7 of the LDLR gene, results from a T to G substitution at nucleotide position 1012. The cysteine at codon 338, located in the EGF-like 1 domain, is replaced by glycine, an amino acid with highly dissimilar properties. Pathogenic LDLR mutations that result in the substitution or generation of cysteine residues within the cysteine-rich LDLR class A repeats and EGF-like domains are common in familial hypercholesterolemia (FH) (Vill&eacute;ger L. Hum Mutat. 2002;20(2):81-7). This particular cysteine alteration (also referred to as p.C317G) has been detected in individuals reported to have hypercholesterolemia (Lombardi MP et al. Clin. Genet., 2000 Feb;57:116-24; van der Graaf A et al. Circulation, 2011 Mar;123:1167-73; Donato LJ et al. J Clin Apher, 2014 Oct;29:256-65). Internal structural analysis indicates this alteration eliminates a disulfide bond critical for the structural integrity of the EGF-like 1 domain (Ambry internal data). In addition, other alterations affecting this codon (e.g., p.C338S, p.C338Y, and p.C338F) have also been reported in association with hypercholesterolemia or in familial hypercholesterolemia cohorts (Maruyama T et al. Arterioscler. Thromb. Vasc. Biol., 1995 Oct;15:1713-8; Lombardi MP et al. Clin. Genet., 2000 Feb;57:116-24; Bourbon M et al. Atherosclerosis, 2017 07;262:8-13). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000237730	SCV000606293	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research