Evidence Repository - Clinical Genome Resources

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.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

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

Uncertain Significance

PM2 BP7 BP4

PM1 PM5

Evidence Links 0

Expert Panel

Familial Hypercholesterolemia VCEP

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.

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.

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.

Approved on: 2023-03-20

Published on: 2023-03-31

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.