Submissions for variant NM_000527.5(LDLR):c.661G>C (p.Asp221His)

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004783179	SCV005394333	likely pathogenic	Familial hypercholesterolemia	2024-09-16	criteria provided, single submitter	clinical testing	Variant summary: LDLR c.661G>C (p.Asp221His) 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 frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.661G>C has been reported in the literature in at least one individual affected with Familial Hypercholesterolemia (Martn-Campos_2018). In addition, another variant (D221G) has been classified as pathogenic in our lab and ClinVar and other variants at the same codon (D221Y, D221N, D221V) have been classified as likely pathogenic/pathogenic in ClinVar, supporting the functional/clinical importance of this residue of the protein. 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: 26755827, 28179607, 30293936). No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as likely pathogenic.