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]

Variant: NM_000527.5(LDLR):c.666C>T (p.Cys222=)

CA505743509

440592 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
Link to MONDO
UUID: 98e5ae0b-297c-4df3-9153-87e79f07cc45
Approved on: 2023-03-20
Published on: 2023-03-31

HGVS expressions

NM_000527.5:c.666C>T
NM_000527.5(LDLR):c.666C>T (p.Cys222=)
NC_000019.10:g.11105572C>T
CM000681.2:g.11105572C>T
NC_000019.9:g.11216248C>T
CM000681.1:g.11216248C>T
NC_000019.8:g.11077248C>T
NG_009060.1:g.21192C>T
ENST00000558518.6:c.666C>T
ENST00000252444.9:n.920C>T
ENST00000455727.6:c.314-1820C>T
ENST00000535915.5:c.543C>T
ENST00000545707.5:c.314-993C>T
ENST00000557933.5:c.666C>T
ENST00000558013.5:c.666C>T
ENST00000558518.5:c.666C>T
ENST00000560467.1:n.266C>T
NM_000527.4:c.666C>T
NM_001195798.1:c.666C>T
NM_001195799.1:c.543C>T
NM_001195800.1:c.314-1820C>T
NM_001195803.1:c.314-993C>T
NM_001195798.2:c.666C>T
NM_001195799.2:c.543C>T
NM_001195800.2:c.314-1820C>T
NM_001195803.2:c.314-993C>T
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Uncertain Significance

Met criteria codes 3
PM2 BP7 BP4
Not Met criteria codes 2
PM1 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.666C>T (p.Cys222=) variant is classified as Uncertain significance - conflicting evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, BP4, BP7) 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: - PM2: PopMax MAF = 0.000008864 (0.0008864%) in European (non-Finnish) exomes (gnomAD v2.1.1). - BP4: No REVEL, splicing evaluation required. Functional data on splicing not available. B) variant is exonic and at least 50bp downstream from canonical acceptor site and creates GT MES scores: de novo variant = 5.19; canonical donor = 7.67. Ratio de novo variant/canonical donor = 5.19/7.67 = 0.67 --- it is below 0.8 Variant is not predicted to alter splicing. - BP7: Variant is synonymous and meets BP4.
Met criteria codes
PM2
PopMax MAF = 0.000008864 (0.0008864%) in European (non-Finnish) exomes (gnomAD v2.1.1).
BP7
Variant is synonymous and meets BP4.
BP4
No REVEL, splicing evaluation required. Functional data on splicing not available. B) variant is exonic and at least 50bp downstream from canonical acceptor site and creates GT MES scores: de novo variant = 5.19; canonical donor = 7.67. Ratio de novo variant/canonical donor = 5.19/7.67 = 0.67 --- it is below 0.8 Variant is not predicted to alter splicing.
Not Met criteria codes
PM1
Even though Cys222 is one of the 60 cysteine residues involved in disulfide bond formation, however, this is synonymous, so PM1 not MET.
PM5
Other pathogenic variants in the same codon, but this is synonymous, so PM5 does not apply.
Curation History
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