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.1855T>C (p.Phe619Leu)

CA037227

252083 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
UUID: 0295e6fb-e527-4826-a143-03161d46853d

HGVS expressions

NM_000527.5:c.1855T>C
NM_000527.5(LDLR):c.1855T>C (p.Phe619Leu)
ENST00000558518.6:c.1855T>C
ENST00000252444.9:n.2109T>C
ENST00000455727.6:c.1351T>C
ENST00000535915.5:c.1732T>C
ENST00000545707.5:c.1474T>C
ENST00000557933.5:c.1855T>C
ENST00000558013.5:c.1855T>C
ENST00000558518.5:c.1855T>C
ENST00000559340.1:n.436T>C
NM_000527.4:c.1855T>C
NM_001195798.1:c.1855T>C
NM_001195799.1:c.1732T>C
NM_001195800.1:c.1351T>C
NM_001195803.1:c.1474T>C
NM_001195798.2:c.1855T>C
NM_001195799.2:c.1732T>C
NM_001195800.2:c.1351T>C
NM_001195803.2:c.1474T>C
NC_000019.10:g.11120101T>C
CM000681.2:g.11120101T>C
NC_000019.9:g.11230777T>C
CM000681.1:g.11230777T>C
NC_000019.8:g.11091777T>C
NG_009060.1:g.35721T>C

Likely Pathogenic

Met criteria codes 5
PS3_Supporting PP4 PP3 PS4_Supporting PM2
Not Met criteria codes 21
BP5 BP7 BP2 BP3 BP4 BP1 PS2 PS1 BA1 PP1 PP2 PM3 PM1 PM4 PM5 PM6 PVS1 BS4 BS3 BS1 BS2

Evidence Links 1

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Familial Hypercholesterolemia VCEP
NM_000527.5(LDLR):c.1855T>C (p.Phe619Leu) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PP4, PS3_Supporting, PS4_Supporting) 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 = 0.00003266 (0.003266%) in East Asian (gnomAD v2.1.1). PP3 - REVEL: 0,857. PP4 - Variant meets PM2. Variant identified in 2 index cases fulfilling validated clinical criteria for FH from different labs. PS3_supporting - PMID: 9409298 - Level 3 assay - study on htz patient's cultured lymphoblasts, immunoblotting + I125-LDL assay, no precursor detectable, degradation of 125I-LDL 63%. ---- functional study is consistent with damaging effect. PS4_supporting - Variant meets PM2. Variant identified in 2 index cases (1 case with Simon-Broome from Color laboratory; 1 case with DLCN criteria from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA)).
Met criteria codes
PS3_Supporting
PMID: 9409298 - Level 3 assay - study on htz patient's cultured lymphoblasts, immunoblotting + I125-LDL assay, no precursor detectable, degradation of 125I-LDL 63%. ---- functional study is consistent with damaging effect

PP4
Variant meets PM2. Variant identified in 2 index cases fulfilling validated clinical criteria for FH (1 case with Simon-Broome from Color laboratory; 1 case with DLCN criteria from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA)).
PP3
REVEL: 0,857. Score is above 0,75.
PS4_Supporting
Variant meets PM2. Variant identified in 2 index cases (1 case with Simon-Broome from Color laboratory; 1 case with DLCN criteria from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA)).
PM2
PopMax MAF = 0.00003266 (0.003266%) in East Asian (gnomAD v2.1.1). MAF is below 0.02%.
Not Met criteria codes
BP5
Not applicable.
BP7
Missense variant. Not applicable.
BP2
Not identified in individuals with other variants.
BP3
Not applicable.
BP4
REVEL: 0,857. Score is not below 0,50.
BP1
Not applicable.
PS2
No de novo cases were identified.
PS1
No variant described that leads to the same amino acid change.
BA1
no FAF, just total MAF = 0.000003976 (0.0004%) in East Asian (gnomAD v2.1.1). MAF is not above 0.5%
PP1
No family members tested.
PP2
Not applicable.
PM3
Not identified in individuals with other variants.
PM1
Missense at codon 619. 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 by these guidelines. Two other missense variants described in the same codon:(1)NM_000527.5(LDLR):c.1856T>G (p.Phe619Cys) (ClinVar ID 252085) - VUS by these guidelines. (2)NM_000527.5(LDLR):c.1856T>C (p.Phe619Ser) (ClinVar ID 252084) - VUS by these guidelines.
PM6
No de novo cases were identified.
PVS1
Missense variant. Not applicable.
BS4
No family members tested.
BS3
No in vitro or in vivo functional studies showing no damaging effect on protein function or splicing.
BS1
no FAF, just total MAF = 0.000003976 (0.0004%) in East Asian (gnomAD v2.1.1). MAF is not above 0.2%
BS2
No unaffected individuals identified with the variant.
Approved on: 2021-06-18
Published on: 2021-06-24
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