Variant: NM_000527.5(LDLR):c.97C>T (p.Gln33Ter)

CA023802

3683 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

UUID: b06630f4-ec3c-49d3-9864-25957fc07c36

Approved on: 2022-03-25

Published on: 2024-12-02

HGVS expressions

NM_000527.5:c.97C>T
NM_000527.5(LDLR):c.97C>T (p.Gln33Ter)
NC_000019.10:g.11100252C>T
CM000681.2:g.11100252C>T
NC_000019.9:g.11210928C>T
CM000681.1:g.11210928C>T
NC_000019.8:g.11071928C>T
NG_009060.1:g.15872C>T
ENST00000252444.10:c.355C>T
ENST00000559340.2:c.97C>T
ENST00000560467.2:c.97C>T
ENST00000558518.6:c.97C>T
ENST00000252444.9:c.351C>T
ENST00000455727.6:c.97C>T
ENST00000535915.5:c.97C>T
ENST00000545707.5:c.97C>T
ENST00000557933.5:c.97C>T
ENST00000557958.1:n.183C>T
ENST00000558013.5:c.97C>T
ENST00000558518.5:c.97C>T
ENST00000560502.5:n.183C>T
NM_000527.4:c.97C>T
NM_001195798.1:c.97C>T
NM_001195799.1:c.97C>T
NM_001195800.1:c.97C>T
NM_001195803.1:c.97C>T
NM_001195798.2:c.97C>T
NM_001195799.2:c.97C>T
NM_001195800.2:c.97C>T
NM_001195803.2:c.97C>T

Pathogenic

• Met criteria codes: PM2 PP1_Strong PVS1 PS4 PS3 PP4

Expert Panel

Familial Hypercholesterolemia VCEP

Criteria Specification Information

Criteria Specification: ClinGen Familial Hypercholesterolemia Expert Panel Specifications to the ACMG/AMP Variant Classification Guidelines Version 1.2

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

NM_000527.5(LDLR):c.97C>T (p.Gln33Ter) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence code PVS1, PS3, PS4, PP1_Strong, PM2 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 25 March 2022. The supporting evidence is as follows: PM2 - PopMax MAF = 0.00001759 (0.002%) in European non-Finnish exomes (gnomAD v2.1.1). PVS1 - Variant leads to stop at codon 33, amino-terminal of amino acid 830. PS3 - Two studies contribute to PS3 attribution. One (PMID:2088165) report a level 2 assay performed on homozygous patient's fibroblasts with radiolabeled LDL consistent with damaging effect of the variant (< 2% LDLR activity). The second reports a level 1 assay performed on Heterologous cells (CHO-ldlA7). FACS, CLSM and WB results in 10% expression, binding and uptake of LDLR which is retained in the ER. PS4 - Variant meets PM2 and is identified in at least 10 unrelated index cases from CGMC UFGOD (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière). 8 cases fulfil SB possible criteria and 14 fulfil DLCN >= 6 criteria. PP1_Strong- Variant segregates with phenotype in >6 informative meioses in >1 family [data from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA) and Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière]: 14 affected family members have the variant. PP4 - Variant meets PM2 and is identified in 22 unrelated index cases from CGMC UFGOD (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière).

Met criteria codes

• PM2: PopMax MAF = 0.00001759 (0,002%) in European non-Finnish exomes (gnomAD v2.1.1).
• PP1_Strong: Variant segregates with phenotype in >6 informative meioses in >1 family [data from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA) and Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière]: 14 affected family members have the variant.
• PVS1: Variant leads to stop at codon 33 amino-terminal of amino acid 830.
• PS4: Variant meets PM2 and is identified in at least 10 unrelated index cases from CGMC UFGOD (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière). 8 cases fulfil SB possible criteria and 14 fulfil DLCN >= 6 criteria.
• PS3: Two studies contribute to PS3 attribution. One (PMID:2088165) report a level 2 assay performed on homozygous patient's fibroblasts with radiolabeled LDL consistent with damaging effect of the variant (< 2% LDLR activity). The second reports a level 1 assay perfomed on Heterologous cells (CHO-ldlA7). FACS, CLSM and WB results in 10% expression, binding and uptake of LDLR which is retained in the ER.
• PP4: Variant meets PM2 and is identified in 22 unrelated index cases from CGMC UFGOD (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière).