Variant: NM_000527.5(LDLR):c.1783C>T (p.Arg595Trp)

CA023581

161290 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

UUID: ba5d5793-ffd3-48df-89c0-24c7600a8a6d

Approved on: 2021-06-09

Published on: 2021-06-24

HGVS expressions

NM_000527.5:c.1783C>T
NM_000527.5(LDLR):c.1783C>T (p.Arg595Trp)
NC_000019.10:g.11116936C>T
CM000681.2:g.11116936C>T
NC_000019.9:g.11227612C>T
CM000681.1:g.11227612C>T
NC_000019.8:g.11088612C>T
NG_009060.1:g.32556C>T
ENST00000558518.6:c.1783C>T
ENST00000252444.9:n.2037C>T
ENST00000455727.6:c.1279C>T
ENST00000535915.5:c.1660C>T
ENST00000545707.5:c.1402C>T
ENST00000557933.5:c.1783C>T
ENST00000558013.5:c.1783C>T
ENST00000558518.5:c.1783C>T
ENST00000559340.1:n.426+724C>T
NM_000527.4:c.1783C>T
NM_001195798.1:c.1783C>T
NM_001195799.1:c.1660C>T
NM_001195800.1:c.1279C>T
NM_001195803.1:c.1402C>T
NM_001195798.2:c.1783C>T
NM_001195799.2:c.1660C>T
NM_001195800.2:c.1279C>T
NM_001195803.2:c.1402C>T

Pathogenic

• Met criteria codes: PS4 PP1_Strong PP4 PP3 PM2

• Not Met criteria codes: PVS1 PS2 PS3 PS1 PP2 PM3 PM1 PM4 PM5 PM6 BA1 BS4 BS3 BS1 BS2 BP5 BP7 BP2 BP3 BP4 BP1

Expert Panel

Familial Hypercholesterolemia VCEP

Criteria Specification Information

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

NM_000527.5(LDLR):c.1783C>T (p.Arg595Trp) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PS4, PP1_Strong, PM2, PP3 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: PS4 - Variant meets PM2. Variant identified in 12 index cases. PP1_strong - 10 informative meioses identified by Laboratory of Genetics and Molecular Cardiology. PM2 - PopMax MAF = 0.00001548 (0.0015%) in European non-Finnish (gnomAD v2.1.1). PP3 - REVEL: 0,89. PP4 - Variant meets PM2. Variant identified in 12 index cases fulfilling validated clinical criteria for FH (6 cases with Simon-Broome or DLCN criteria from Ambry Genetics; 2 cases with Simon-Broome from Color laboratory; 3 cases with Simon-Broome criteria from Laboratory of Genetics and Molecular Cardiology; 1 case with Simon-Broome criteria from GeneDx).

Met criteria codes

• PS4: Variant meets PM2. Variant identified in 12 index cases (6 cases with Simon-Broome or DLCN criteria from Ambry Genetics; 2 cases with Simon-Broome from Color laboratory; 3 cases with Simon-Broome criteria from Laboratory of Genetics and Molecular Cardiology; 1 case with Simon-Broome criteria from GeneDx).
• PP1_Strong: 10 informative meioses identified by Laboratory of Genetics and Molecular Cardiology.
• PP4: Variant meets PM2. Variant identified in 12 index cases fulfilling validated clinical criteria for FH (See PS4).
• PP3: REVEL: 0,89. Score is above 0,75.
• PM2: PopMax MAF = 0.00001548 (0.0015%) in European non-Finnish (gnomAD v2.1.1). MAF is below 0.02%.

Not Met criteria codes

• PVS1: Missense variant. Not applicable.
• PS2: No de novo cases were identified.
• PS3: No functional assays performed/found - not applicable.
• PS1: No variant described that leads to the same amino acid change.
• PP2: Not applicable.
• PM3: 1 index case from Laboratory of Genetics and Molecular Cardiology is a compound heterozygote in trans with the NM_000527.5(LDLR):c.1217G>C (p.Arg406Pro) variant, phenotype similar to HoFH (LDLc 405 mg/dL treated). Unsuficient information about nontreated levels of LDLc. PM3 is not met.
• PM1: Missense at codon 595. PM2 is Met, but it is not exon 4 or any of the 60 Cys residues listed. Not applicable.
• PM4: Missense variant. Not applicable.
• PM5: No other missense variants classified as Pathogenic in the same codon. Two other missense variants described in the same codon (accessed 19 August 2020): (1)NM_000527.5(LDLR):c.1784G>T (p.Arg595Leu) (ClinVar ID 252029) - classified as VUS by these guidelines. (2)NM_000527.5(LDLR):c.1784G>A (p.Arg595Gln) (ClinVar ID 183126) - classified as VUS by these guidelines.
• PM6: No de novo cases were identified.
• BA1: no FAF, just total MAF = 0.000003976 (0.0004%) in European non-Finnish (gnomAD v2.1.1). MAF is not above 0.5%
• BS4: No non-segregations were identified/found.
• BS3: No functional assays performed/found - not applicable.
• BS1: no FAF, just total MAF = 0.000003976 (0.0004%) in European non-Finnish (gnomAD v2.1.1). MAF is not above 0.5%
• BS2: No unaffected individuals identified with the variant.
• BP5: Not applicable.
• BP7: Missense variant. Not applicable.
• BP2: 1 index case from Laboratory of Genetics and Molecular Cardiology is a compound heterozygote in trans with the NM_000527.5(LDLR):c.1217G>C (p.Arg406Pro) variant, phenotype similar to HoFH (LDLc 405 mg/dL treated). BP2 is not met.
• BP3: Not applicable.
• BP4: REVEL: 0,89. Score is not below 0,15.
• BP1: Not applicable.