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.440C>T (p.Thr147Ile)

CA10584919

251223 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
Link to MONDO
UUID: 3519a731-8d76-4cd2-8333-2d0d1c76ac46
Approved on: 2023-04-28
Published on: 2023-04-30

HGVS expressions

NM_000527.5:c.440C>T
NM_000527.5(LDLR):c.440C>T (p.Thr147Ile)
NC_000019.10:g.11105346C>T
CM000681.2:g.11105346C>T
NC_000019.9:g.11216022C>T
CM000681.1:g.11216022C>T
NC_000019.8:g.11077022C>T
NG_009060.1:g.20966C>T
ENST00000558518.6:c.440C>T
ENST00000252444.9:n.694C>T
ENST00000455727.6:c.314-2046C>T
ENST00000535915.5:c.317C>T
ENST00000545707.5:c.314-1219C>T
ENST00000557933.5:c.440C>T
ENST00000558013.5:c.440C>T
ENST00000558518.5:c.440C>T
ENST00000560467.1:n.40C>T
NM_000527.4:c.440C>T
NM_001195798.1:c.440C>T
NM_001195799.1:c.317C>T
NM_001195800.1:c.314-2046C>T
NM_001195803.1:c.314-1219C>T
NM_001195798.2:c.440C>T
NM_001195799.2:c.317C>T
NM_001195800.2:c.314-2046C>T
NM_001195803.2:c.314-1219C>T
More

Likely Pathogenic

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Insufficient Evidence"
Met criteria codes 4
PP3 PS3_Supporting PM1 PM2
Not Met criteria codes 15
PP4 PP1 BA1 PM4 PM5 PM6 BS2 BS4 BS3 BS1 BP3 BP4 PS2 PS4 PS1

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.440C>T (p.Thr147Ile) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes PS3_Supporting, PM1, PM2, and PP3 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: PS3_Supporting: Level 3 assays: PMID 21865347: Htz Patient lymphocytes, FACS assays - results - 55-70% LDLR activity ---- results are below 85% of wild-type activity. So PS3_Supporting is met. PM1: Variant meets PM2 and is on exon 4. So PM1 is met. PM2: This variant is absent from gnomAD (gnomAD v2.1.1). So PM2 is met. PP3: REVEL = 0.811. It is above 0.75, so PP3 is met.
Met criteria codes
PP3
REVEL = 0.811. It is above 0.75, so PP3 is met.
PS3_Supporting
Level 3 assays: PMID 21865347: Htz Patient lymphocytes, FACS assays - results - 55-70% LDLR activity ---- results are below 85% of wild-type activity. So PS3_Supporting is met.
PM1
Variant meets PM2 and is on exon 4. So PM1 is met.
PM2
This variant is absent from gnomAD (gnomAD v2.1.1). So PM2 is met.
Not Met criteria codes
PP4
No data available
PP1
No data available
BA1
This variant is absent from gnomAD (gnomAD v2.1.1).
PM4
No in-frame deletions/insertions.
PM5
No other missense variant in the same codon.
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS2
No data available
BS4
No data available
BS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS1
This variant is absent from gnomAD (gnomAD v2.1.1).
BP3
No in-frame deletions/insertions.
BP4
REVEL = 0.811. It is above 0.5
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4
No data available
PS1
No other missense variant in the same codon.
Curation History
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