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]
Link to SEPIO compliant JSON-LD document

Variant: NM_000527.5(LDLR):c.665G>T (p.Cys222Phe)

CA10585053

251362 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
Link to MONDO
UUID: 9bd3b83b-b8ff-4ed8-84d5-c0735c0618bb

HGVS expressions

NM_000527.5:c.665G>T
NM_000527.5(LDLR):c.665G>T (p.Cys222Phe)
NC_000019.10:g.11105571G>T
CM000681.2:g.11105571G>T
NC_000019.9:g.11216247G>T
CM000681.1:g.11216247G>T
NC_000019.8:g.11077247G>T
NG_009060.1:g.21191G>T
ENST00000558518.6:c.665G>T
ENST00000252444.9:n.919G>T
ENST00000455727.6:c.314-1821G>T
ENST00000535915.5:c.542G>T
ENST00000545707.5:c.314-994G>T
ENST00000557933.5:c.665G>T
ENST00000558013.5:c.665G>T
ENST00000558518.5:c.665G>T
ENST00000560467.1:n.265G>T
NM_000527.4:c.665G>T
NM_001195798.1:c.665G>T
NM_001195799.1:c.542G>T
NM_001195800.1:c.314-1821G>T
NM_001195803.1:c.314-994G>T
NM_001195798.2:c.665G>T
NM_001195799.2:c.542G>T
NM_001195800.2:c.314-1821G>T
NM_001195803.2:c.314-994G>T

Likely Pathogenic

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Insufficient Evidence"
Met criteria codes 6
PS3_Moderate PP4 PP3 PS4_Supporting PM2 PM1
Not Met criteria codes 16
PVS1 BS2 BS4 BS3 BS1 BP7 BP2 BP4 PS2 PS1 BA1 PP1 PM6 PM3 PM4 PM5

Evidence Links 0

Expert Panel

Criteria Specification Information

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

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Familial Hypercholesterolemia VCEP
The NM_000527.5(LDLR):c.665G>T (p.Cys222Phe) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes PM1, PM2, PS3_Moderate, PP3, PP4, PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM1: Variant meets PM2 and is missense in exon 4 PM2: This variant is absent from gnomAD v 2.1.1. PS3_Moderate: PMID: 24671153 Heterologous cells, 30 % cell surface LDLR and internalization PP3: REVEL is 0.971, which is greater than 0.75. PP4: Variant meets PM2 and is identified in at least 1 index case who fulfills DLCN>=6 criteria for FH from PMID 24671153, after alternative causes of high cholesterol were excluded.. PS4_Supporting: Variant meets PM2 and is identified in at least 2 unrelated index cases. 1 index case from PMID 11810272 who fulfilled unspecified clinical criteria for FH, and 1 index case from PMID 24671153 who fulfilled DLCN>6 criteria for FH.
Met criteria codes
PS3_Moderate
PMID: 24671153 Heterologous cells, 30 % cell surface LDLR and internalization
PP4
Variant meets PM2 and is identified in at least 1 index case who fulfills DLCN>=6 criteria for FH from PMID 24671153, after alternative causes of high cholesterol were excluded.
PP3
REVEL is 0.971, which is greater than 0.75.
PS4_Supporting
Variant meets PM2 and is identified in at least 2 unrelated index cases. 1 index case from PMID 11810272 who fulfilled unspecified clinical criteria for FH, and 1 index case from PMID 24671153 who fulfilled DLCN>6 criteria for FH.
PM2
This variant is absent from gnomAD v 2.1.1.
PM1
Variant meets PM2 and is missense in exon 4
Not Met criteria codes
PVS1
Not met.
BS2
Not met.
BS4
Not met.
BS3
Not met.
BS1
Not met.
BP7
Not met.
BP2
Not met.
BP4
Not met.
PS2
Not met.
PS1
Not met.
BA1
Not met.
PP1
Not met.
PM6
Not met.
PM3
Not met.
PM4
Not met.
PM5
Not met.
Approved on: 2023-04-28
Published on: 2023-04-30
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