Variant: c.(?_-187)_(190+1_191-1)del

250933 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

UUID: 81e3eb12-5953-408f-8622-140cbae0308e

HGVS expressions

Pathogenic

• Met criteria codes: PVS1 PS4 PP4 PS3_Supporting PP1_Moderate PM2

• Not Met criteria codes: PM3

Expert Panel

Familial Hypercholesterolemia VCEP

Criteria Specification Information

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

The NM_000527.5 (LDLR):c.(?_-187)_(190+1_191-1)del variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PVS1, PS3_Supporting, PP4, PS4, PP1_Moderate) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v2.1.1). PVS1: Deletion of exons 1 and 2 that lead to an out-of-frame consequence. PS3_Supporting: Level 3 assay performed using heterozygous patient cells in 125I-LDL assay showed 45% LDLR activity (Sezione di Patologia General, Dipartimento di Scienze Biomediche, Universita di Modena, Italy, PMID 8678915). Functional study is consistent with damaging effect. PP4: This variant meets PM2 and is identified in >1 index case who met clinical criteria for FH after alternative causes for high cholesterol were excluded. PS4: Variant meets PM2 and is identified in 22 unrelated index cases. Eighteen unrelated index cases fulfil Simon Broome criteria (Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge); 1 index case met Simon Broome possible FH criteria (Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation); 2 index cases met DLCN criteria (1 case each from Ambry Genetics, and Sezione di Patologia General, Dipartimento di Scienze Biomediche, Universita di Modena, Italy, PMID: 8678915); 1 index case met criteria of total and LDL-C levels over the 95th percentile corrected for age and sex, plus two of: tendon xanthomata, premature coronary heart disease in the proband or in a first-degree relative and hypercholesterolemic children in the family (Instituto de Investigaciones Citológicas, Fundación Valenciana de Investigaciones Biomédicas, Valencia, Spain, PMID 11668640). PP1_moderate: Variant segregates with FH phenotype in 5 informative meiosis from 2 families: 2 affected relatives tested positive for the variant from one family (Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation); 2 affected relatives tested positive and 1 unaffected relative tested negative for the variant from one family ( Sezione di Patologia General, Dipartimento di Scienze Biomediche, Universita di Modena, Italy, PMID 8678915).

Met criteria codes

• PVS1: Deletion of exons 1 and 2 that lead to an out-of-frame consequence.
• PS4: Variant meets PM2 and is identified in 22 unrelated index cases. Eighteen unrelated index cases fulfil Simon Broome criteria (Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge); 1 index case met Simon Broome possible FH criteria (Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation); 2 index cases met DLCN criteria (1 case each from Ambry Genetics, and Sezione di Patologia General, Dipartimento di Scienze Biomediche, Universita di Modena, Italy, PMID: 8678915); 1 index case met criteria of total and LDL-C levels over the 95th percentile corrected for age and sex, plus two of: tendon xanthomata, premature coronary heart disease in the proband or in a first-degree relative and hypercholesterolemic children in the family (Instituto de Investigaciones Citológicas, Fundación Valenciana de Investigaciones Biomédicas, Valencia, Spain, PMID 11668640).
• PP4: This variant meets PM2 and is identified in >1 index case who met clinical criteria for FH after alternative causes for high cholesterol were excluded.
• PS3_Supporting: Level 3 assay performed using heterozygous patient cells in 125I-LDL assay showed 45% LDLR activity (Sezione di Patologia General, Dipartimento di Scienze Biomediche, Universita di Modena, Italy, PMID 8678915). Functional study is consistent with damaging effect.
• PP1_Moderate: Variant segregates with FH phenotype in 5 informative meiosis from 2 families: 2 affected relatives tested positive for the variant from one family (Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation); 2 affected relatives tested positive and 1 unaffected relative tested negative for the variant from one family ( Sezione di Patologia General, Dipartimento di Scienze Biomediche, Universita di Modena, Italy, PMID 8678915).
• PM2: This variant is absent from gnomAD (gnomAD v2.1.1).

Not Met criteria codes

• PM3: Variant meets PM2 and is identified in an index case with homozygous genotype. Although the patient was reported being part of a HoFH study, but no clinical information available (Ambry Genetics).

Approved on: 2022-03-25

Published on: 2022-04-25