ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.974G>A (p.Cys325Tyr) (rs879254746)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000238286 SCV000295121 likely pathogenic Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
Fundacion Hipercolesterolemia Familiar RCV000238286 SCV000607539 likely pathogenic Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000588581 SCV000697256 likely pathogenic Familial hypercholesterolemia 2016-05-05 criteria provided, single submitter clinical testing Variant summary: The LDL receptor (encoded by LDLR gene) is an 839-amino acid protein rich in cysteine. The LDLR c.974G>A variant affects a conserved nucleotide, resulting in amino acid change from Cys to Tyr at codon 325. Cys325 is a highly conserved residue located in the EGF-like calcium-binding domain of the LDL receptor. HGMD lists >50 Cys missense mutations reported in the literature as associated with hypercholesterolaemia, and 5/5 in-silico tools predict damaging outcome for this variant. This variant was not found in 120534 control chromosomes, but has been reported in at least 2 affected individuals in the literature, and was shown to have significantly decreased LDLR residual activity in EBV-transformed B-lymphocytes and stimulated T-lymphocytes (Romano_JLR_2011). Furthermore, other missense changes at this position (i.e. p.Cys325Phe) have been reported in hypercholesterolaemia patients (PMID: 26802169), suggesting changes at Cys 325 are not tolerated. Taken together, this variant was classified as likely pathogenic until additional clinical information is available.
Brunham Lab, Centre for Heart and Lung Innovation,University of British Columbia RCV000238286 SCV001432620 pathogenic Familial hypercholesterolemia 1 2019-06-05 criteria provided, single submitter research
Invitae RCV000588581 SCV001544522 uncertain significance Familial hypercholesterolemia 2020-01-08 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tyrosine at codon 325 of the LDLR protein (p.Cys325Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with familial hypercholesterolemia or early-onset coronary artery disease (PMID: 30526649, 21865347). ClinVar contains an entry for this variant (Variation ID: 251580). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Benign; Align-GVGD: Class C). 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). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 6
Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II RCV000238286 SCV001653614 likely pathogenic Familial hypercholesterolemia 1 2021-05-24 criteria provided, single submitter clinical testing Reduced activity, in stimulated T-lymphocytes and EBV-transformed B-lymphocytes.

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