Variant: NM_000527.5(LDLR):c.1216C>T (p.Arg406Trp)

CA033073

226351 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

UUID: 20341145-6ce8-4ebf-bf2f-1b567994c9fb

Approved on: 2022-05-19

Published on: 2022-05-19

HGVS expressions

NM_000527.5:c.1216C>T
NM_000527.5(LDLR):c.1216C>T (p.Arg406Trp)
NC_000019.10:g.11113307C>T
CM000681.2:g.11113307C>T
NC_000019.9:g.11223983C>T
CM000681.1:g.11223983C>T
NC_000019.8:g.11084983C>T
NG_009060.1:g.28927C>T
ENST00000558518.6:c.1216C>T
ENST00000252444.9:n.1470C>T
ENST00000455727.6:c.712C>T
ENST00000535915.5:c.1093C>T
ENST00000545707.5:c.835C>T
ENST00000557933.5:c.1216C>T
ENST00000558013.5:c.1216C>T
ENST00000558518.5:c.1216C>T
ENST00000560173.1:n.215C>T
ENST00000560467.1:n.696C>T
NM_000527.4:c.1216C>T
NM_001195798.1:c.1216C>T
NM_001195799.1:c.1093C>T
NM_001195800.1:c.712C>T
NM_001195803.1:c.835C>T
NM_001195798.2:c.1216C>T
NM_001195799.2:c.1093C>T
NM_001195800.2:c.712C>T
NM_001195803.2:c.835C>T

Pathogenic

• Met criteria codes: PP1_Strong PM2 PS4 PS3 PP4 PP3

• Not Met criteria codes: BA1 PM3 PM1 PM4 PM5 PM6 BS2 BS4 BS3 BS1 BP2 BP4 BP7 PVS1 PS2 PS1

Expert Panel

Familial Hypercholesterolemia VCEP

Criteria Specification Information

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

The NM_000527.5(LDLR):c1216C>T (p.Arg406Trp) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PP3, PS3, PS4, PP1_Strong, and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PM2 - PopMax MAF = 0.000097 (0.0097%) in Ashkenazi Jewish exomes+genomes (gnomAD v2.1.1). PP3 - REVEL = 0.88, which is above the threshold of 0.75. PS3 – Level 1 functional studies: PMID: 2574186; Heterologous cells (CHO), FACS assays - variant results in 60-65% LDLR expression/biosynthesis, LDL binding and LDL internalization compared to wild-type; results meet <70% threshold. PS4 – Variant meets PM2 and is identified in at least 19 unrelated index cases who fulfill clinical criteria for FH (1 case with DLCN criteria from PathWest Laboratory Medicine WA – FH VCEP member lab; 18 cases with SB criteria from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge – FH VCEP member lab). PP1_Strong – Variant segregates with phenotype in 31 informative meioses from 15 families in data provided by FH VCEP member labs (Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge – 11 families: 23 affected with the variant and 1 unaffected without the variant; Laboratory of Genetics and Molecular Cardiology – 4 families: 4 affected with the variant and 3 unaffected without the variant). PP4 - Variant meets PM2. Identified in >1 case who met clinical criteria for FH after alternative causes for high cholesterol were excluded. Note: two other missense variants at this same codon have been reported: 1) NM_000527.5(LDLR):c.1217G>A (p.Arg406Gln) – Likely pathogenic by these guidelines. 2) NM_000527.5(LDLR):c.1217G>C (p.Arg406Pro) – Likely pathogenic by these guidelines. -PM5 not applicable as such variants must be Pathogenic.

Met criteria codes

• PP1_Strong: Variant segregates with phenotype in 31 informative meioses from 15 families in data provided by FH VCEP member labs (Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge – 11 families: 23 affected with the variant and 1 unaffected without the variant; Laboratory of Genetics and Molecular Cardiology – 4 families: 4 affected with the variant and 3 unaffected without the variant)
• PM2: PopMax MAF = 0.000097 (0.0097%) in Ashkenazi Jewish exomes+genomes (gnomAD v2.1.1).
• PS4: Variant meets PM2 and is identified in at least 19 unrelated index cases who fulfill clinical criteria for FH (1 case with DLCN criteria from PathWest Laboratory Medicine WA – FH VCEP member lab; 18 cases with SB criteria from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge – FH VCEP member lab).
• PS3: Level 1 studies performed: PMID: 2574186; Heterologous cells (CHO), FACS assays - variant results in 60-65% LDLR expression/biosynthesis, LDL binding AND LDL internalization compared to wild-type; results meet <70% threshold.
• PP4: Variant meets PM2. Identified in >1 case who met clinical criteria for FH after alternative causes for high cholesterol were excluded.
• PP3: REVEL = 0.88

Not Met criteria codes

• BA1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM5: 2 other missense variants in the same codon: 1) NM_000527.5(LDLR):c.1217G>A (p.Arg406Gln) – Likely pathogenic by these guidelines. 2) NM_000527.5(LDLR):c.1217G>C (p.Arg406Pro) - Likely pathogenic by these guidelines.
• PM6: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS4: No genotype-positive, phenotype-negative cases, which are required for BS4.
• BS3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP7: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PVS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline