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]

Variant: NM_000527.5(LDLR):c.2225C>T (p.Thr742Ile)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA039172

252259 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 7fd2722f-13aa-411c-8ef0-c03ac2056b5e

Approved on: 2025-02-28

Published on: 2025-04-08

HGVS expressions

NM_000527.5:c.2225C>T

NM_000527.5(LDLR):c.2225C>T (p.Thr742Ile)

NC_000019.10:g.11123258C>T

CM000681.2:g.11123258C>T

NC_000019.9:g.11233934C>T

CM000681.1:g.11233934C>T

NC_000019.8:g.11094934C>T

NG_009060.1:g.38878C>T

ENST00000252444.10:c.2483C>T

ENST00000559340.2:c.*294C>T

ENST00000560467.2:c.2105C>T

ENST00000558518.6:c.2225C>T

ENST00000252444.9:c.2479C>T

ENST00000455727.6:c.1721C>T

ENST00000535915.5:c.2102C>T

ENST00000545707.5:c.1691C>T

ENST00000557933.5:c.2225C>T

ENST00000558013.5:c.2225C>T

ENST00000558518.5:c.2225C>T

NM_000527.4:c.2225C>T

NM_001195798.1:c.2225C>T

NM_001195799.1:c.2102C>T

NM_001195800.1:c.1721C>T

NM_001195803.1:c.1691C>T

NM_001195798.2:c.2225C>T

NM_001195799.2:c.2102C>T

NM_001195800.2:c.1721C>T

NM_001195803.2:c.1691C>T

Uncertain Significance

PP4 PM2 PS4_Supporting

PP3 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

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Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

The NM_000527.5(LDLR):c.2225C>T (p.Thr742Ile) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP4 and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on February 28, 2025. The supporting evidence is as follows: PM2: PopMax MAF = 0.000003390 (0.0003390%) in European (non-Finnish) exomes + genomes (gnomAD v4.1.0). PS4_Supporting, PP4: Variant meets PM2 and is identified in 2 unrelated index cases who fulfill Simon Broome criteria for possible FH after alternative causes of high cholesterol were excluded (1 case from PMID 11462246 (Nauck et al., 2001), Germany; 1 case from PMID 17142622 (Humphries et al., 2006), UK).

PP4

Variant meets PM2 and is identified in at least 1 index case who fulfills SB possible FH, after alternative causes of high cholesterol were excluded (PMID 11462246).

PM2

PopMax MAF = 0.000003390 (0.0003390 %) in European (non-Finnish) exomes (gnomAD v4.1.0).

PS4_Supporting

Variant meets PM2 and is identified in 2 unrelated index cases who fulfill SB possible FH after alternative causes of high cholesterol were excluded (PMIDs 11462246 and 17142622). (1) 1 index case who fulfills SB possible FH from PMID 11462246 (2) 1 index case who fulfills SB possible FH from PMID 17142622

PP3

REVEL = 0.552, it is not above 0.75, splicing evaluation required. Functional data on splicing not available. A) not on limits B) it does not create AG/GT C) There is no AG/GT nearby. Variant is not predicted to alter splicing.

PM5

Although there are other variants reported in the same codon, none are classified as Pathogenic by these guidelines.

Curation History

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