Description
The c.1327T>C (p.W443R) alteration is located in exon 9 (coding exon 9) of the LDLR gene. This alteration results from a T to C substitution at nucleotide position 1327, causing the tryptophan (W) at amino acid position 443 to be replaced by an arginine (R). Based on data from gnomAD, the C allele has an overall frequency of 0.001% (1/251246) total alleles studied. The highest observed frequency was 0.001% (1/113560) of European (non-Finnish) alleles. This variant was identified in trans with a second LDLR variant in twins presenting with elevated LDL-C levels and multiple xanthomas (Zhang, 2022). It was also reported in conjunction with a gross deletion in an individual with elevated LDL-C levels and a history of myocardial infarction at age 21 years (Semenova, 2020). In addition, this variant has been identified alone in Russian individuals with elevated LDL-C levels (Korneva, 2017; Meshkov, 2021). This amino acid position is highly conserved in available vertebrate species. Internal structural analysis indicates that this variant, which impacts a conserved residue in the YWTD motif of an LDLR class B repeat, is structurally disruptive (Lo Surdo, 2011; Ambry internal data). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
# | Sample | Method | Observation |
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Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences |
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1 | germline | unknown | not provided | not provided | not provided | | not provided | not provided | not provided | not provided |