Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • See Evidence submitted by expert panel for details.

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

CA023581

161290 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
Link to MONDO
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
ENST00000252444.10:c.2041C>T
ENST00000559340.2:c.1705+724C>T
ENST00000560467.2:c.1663C>T
ENST00000558518.6:c.1783C>T
ENST00000252444.9:c.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:c.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
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Pathogenic

Met criteria codes 5
PP1_Strong PS4 PP3 PP4 PM2
Not Met criteria codes 21
PVS1 BA1 BS2 BS1 BS4 BS3 BP4 BP3 BP1 BP2 BP5 BP7 PS1 PS2 PS3 PP2 PM1 PM3 PM5 PM4 PM6

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
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
PP1_Strong
10 informative meioses identified by Laboratory of Genetics and Molecular Cardiology.
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).
PP3
REVEL: 0,89. Score is above 0,75.
PP4
Variant meets PM2. Variant identified in 12 index cases fulfilling validated clinical criteria for FH (See PS4).
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.
BA1
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.
BS1
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.
BP4
REVEL: 0,89. Score is not below 0,15.
BP3
Not applicable.
BP1
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.
BP5
Not applicable.
BP7
Missense variant. Not applicable.
PS1
No variant described that leads to the same amino acid change.
PS2
No de novo cases were identified.
PS3
No functional assays performed/found - not applicable.
PP2
Not applicable.
PM1
Missense at codon 595. PM2 is Met, but it is not exon 4 or any of the 60 Cys residues listed. 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.
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.
PM4
Missense variant. Not applicable.
PM6
No de novo cases were identified.
Curation History
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