Submissions for variant NM_000527.5(LDLR):c.223T>A (p.Cys75Ser)

gnomAD frequency: 0.00001  dbSNP: rs879254439

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000237232	SCV000294535	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Labcorp Genetics (formerly Invitae), Labcorp	RCV000775026	SCV000627031	pathogenic	Familial hypercholesterolemia	2025-01-11	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 75 of the LDLR protein (p.Cys75Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypercholesterolemia (PMID: 10089940; internal data). 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 C54S. ClinVar contains an entry for this variant (Variation ID: 251079). 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.Cys75 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 9676383, 10089940, 12124988, 17094996; internal data), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000775026	SCV000909123	likely pathogenic	Familial hypercholesterolemia	2019-03-12	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Cys54Ser in the mature protein) is located in the second LDLR type A repeat of the ligand binding domain of 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 for this variant, it changes one of the functionally critical cysteine residues that form intra-repeat disulfide bonds in the ligand binding domain (PMID: 15952897) and is expected to have deleterious impact on the LDLR protein folding and stability. This variant has been identified in an individual diagnosed with familial hypercholesterolemia in U.S. (PMID: 10089940). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Likely Pathogenic.
GeneDx	RCV001582800	SCV001810974	likely pathogenic	not provided	2024-04-02	criteria provided, single submitter	clinical testing	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; Also known as p.(C54S); This variant is associated with the following publications: (PMID: 35913489, 34037665, 2988123, 12459547, 10089940)
Ambry Genetics	RCV002429164	SCV002727963	likely pathogenic	Cardiovascular phenotype	2023-10-04	criteria provided, single submitter	clinical testing	The p.C75S variant (also known as c.223T>A), located in coding exon 3 of the LDLR gene, results from a T to A substitution at nucleotide position 223. The cysteine at codon 75 is replaced by serine, an amino acid with 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) (Villéger L et al. Hum Mutat. 2002;20(2):81-7). This particular cysteine alteration (also referred to as C54S) has been described in a proband with LDL-C level of 298mg/dL, in a Slovenian pediatric hypercholesterolemia cohort, and in additional probands referred for FH genetic testing (Emi M et al. Jpn Heart J. 1998;39(6):785-789; Klanar G et al. J. Am. Coll. Cardiol. 2015;66(11):1250-1257; external communication). Internal structural analysis indicates this alteration eliminates a disulfide bond critical for the structural integrity of LDLR class A repeat 2 (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000237232	SCV004848146	likely pathogenic	Hypercholesterolemia, familial, 1	2020-04-08	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000775026	SCV005203072	likely pathogenic	Familial hypercholesterolemia	2024-07-09	criteria provided, single submitter	clinical testing	Variant summary: LDLR c.223T>A (p.Cys75Ser) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251492 control chromosomes. c.223T>A has been reported in the literature in the heterozygous state in multiple individuals and in the presumed compound heterozygous state in at least 1 indivdiual affected with Familial Hypercholesterolemia (example, Cuchel_2023, Emi_1998, Klancar_2015, Sturm_2021, Sustar_2022). These data indicate that the variant may be associated with disease. Additionally, a different missense variant at the same codon (p.Cys75Tyr) has been classified as Likely Pathogenic/Pathogenic by all laboratories in ClinVar, suggesting this residue is clinically important. 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: 37119068, 10089940, 26361156, 34037665, 35913489). ClinVar contains an entry for this variant (Variation ID: 251079). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000237232	SCV005398755	pathogenic	Hypercholesterolemia, familial, 1	2022-09-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with familial hypercholesterolaemia 1 (FH; MIM#143890). (I) 0108 - This gene is associated with both recessive and dominant disease. Variants have been reported in heterozygous, compound heterozygous and homozygous states, with recessive disease being more severe (OMIM, PMID: 10978268). (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID: 24404629). (I) 0200 - Variant is predicted to result in a missense amino acid change from cysteine to serine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 (v3) (1 heterozygote, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0601 - Variant is located in the well-established functional LDLR-A domain and affects a cysteine residue. Cysteine residues in the LDLR-A domains have been shown to form disulphide bonds which are critical for the structure and stability of the protein (DECIPHER, NCBI, PMIDs: 7548065, 15952897). (SP) 0703 - Other missense variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. p.(Cys75Tyr) has been classified as pathogenic by a clinical laboratory in ClinVar, and p.(Cys75Trp) has been observed in an individual with FH (PMID: 17094996). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic and likely pathogenic by clinical laboratories in ClinVar, and has been observed in two heterozygous individuals with FH in the literature (PMIDs: 10089940, 34327453). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001582800	SCV005625835	likely pathogenic	not provided	2023-12-04	criteria provided, single submitter	clinical testing	The LDLR c.223T>A (p.Cys75Ser) variant has been reported in the published literature in individuals with hypercholesterolemia (PMID: 10089940 (1998), 9676383 (1998), PMID: 34037665 (2021)) as well as in pediatric individuals with hypercholesterolemia (PMID: 26361156 (2015), 35913489 (2022)). This variant affects one of the cysteine residues located in LDL Receptor Domain Class A (LDLa) repeat 2 that form disulfide bonds causing a LDLR protein folding defect (PMID: 34906454 (2022)). 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 likely pathogenic.