ClinVar Miner

Submissions for variant NM_000527.4(LDLR):c.1066G>A (p.Asp356Asn) (rs767767730)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000522393 SCV000617507 uncertain significance not provided 2017-11-02 criteria provided, single submitter clinical testing The D356N variant in the LDLR gene (also reported as D335N due to alternate nomenclature) has published previously in one individual with FH, with total cholesterol in the 96.2 percentile (8.8 mmol/L) and with high LDL-C (6.4 mmol/L) (Alharbi et al., 2005). However, D356N has also reported as a non-pathogenic variant" identified in a cohort of Polish individuals with FH (Chmara et al., 2010). The D356N variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The D356N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. Although this substitution occurs at a position that is not conserved with asparagine (N) tolerated at this position in several species, in silico analysis predicts this variant is probably damaging to the protein structure/function. Another missense variant at the same residue (D356A) has been reported in association with FH, supporting the functional importance of this residue of the protein (Marduel et al., 2010). Nevertheless, the D356N variant lacks sufficient evidence, including observation in a significant number of affected individuals, segregation studies, and functional characterization, that would further clarify its potential pathogenicity."
LDLR-LOVD, British Heart Foundation RCV000238202 SCV000295195 likely benign Familial hypercholesterolemia 2016-03-25 criteria provided, single submitter literature only
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000238202 SCV000606315 pathogenic Familial hypercholesterolemia no assertion criteria provided research

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