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.1322T>C (p.Ile441Thr)

CA10585400

251783 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: c86aaf4e-cc4f-448f-a070-bdbdce293339

HGVS expressions

NM_000527.5:c.1322T>C

NM_000527.5(LDLR):c.1322T>C (p.Ile441Thr)

ENST00000558518.6:c.1322T>C

ENST00000252444.9:n.1576T>C

ENST00000455727.6:c.818T>C

ENST00000535915.5:c.1199T>C

ENST00000545707.5:c.941T>C

ENST00000557933.5:c.1322T>C

ENST00000558013.5:c.1322T>C

ENST00000558518.5:c.1322T>C

ENST00000559340.1:n.43T>C

ENST00000560173.1:n.321T>C

ENST00000560467.1:n.802T>C

NM_000527.4:c.1322T>C

NM_001195798.1:c.1322T>C

NM_001195799.1:c.1199T>C

NM_001195800.1:c.818T>C

NM_001195803.1:c.941T>C

NM_001195798.2:c.1322T>C

NM_001195799.2:c.1199T>C

NM_001195800.2:c.818T>C

NM_001195803.2:c.941T>C

NC_000019.10:g.11113413T>C

CM000681.2:g.11113413T>C

NC_000019.9:g.11224089T>C

CM000681.1:g.11224089T>C

NC_000019.8:g.11085089T>C

NG_009060.1:g.29033T>C

Pathogenic

PP1_Strong PS4_Moderate PS3 PP4 PP3 PM2

PVS1 BA1 BS2 BS4 BS3 BS1 BP5 BP7 BP2 BP3 BP4 BP1 PS2 PS1 PP2 PM6 PM3 PM1 PM4 PM5

Evidence Links 0

Expert Panel

Familial Hypercholesterolemia VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

NM_000527.5(LDLR):c.1322T>C (p.Ile441Thr) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PS3, PP1_Strong, PM2, PS4_Moderate, PP3 and PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PS3 - Level 1 assay - PMID:25741862 - CHO cells, WB+FACS+CLSM, 7% low-density lipoprotein particle receptor biosynthetic process; 5% low-density lipoprotein particle binding; 10% low-density lipoprotein particle clearance. PP1_strong - 6 informative meioses in 3 families identified by Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge. PM2 - No population data was found for this allele in gnomAD (gnomAD v2.1.1). PS4_moderate - Variant meets PM2. Variant identified in 9 index cases. PP3 - REVEL: 0,907. PP4 - Variant meets PM2. Variant identified in 9 index cases fulfilling specific clinical criteria for FH (6 cases with Simon-Broome from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge; 3 cases with Simon-Broome criteria published in PMID: 20538126).

PP1_Strong

6 informative meioses in 3 families identified by Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge.

PS4_Moderate

Variant meets PM2. Variant identified in 9 index cases (6 cases with Simon-Broome from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge; 3 cases with Simon-Broome criteria published in PMID: 20538126).

PS3

Level 1 assay - PMID:25741862 - CHO cells, WB+FACS+CLSM, 7% low-density lipoprotein particle receptor biosynthetic process; 5% low-density lipoprotein particle binding; 10% low-density lipoprotein particle clearance

PP4

Variant meets PM2. Variant identified in 9 index cases fulfilling specific clinical criteria for FH (6 cases with Simon-Broome from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge; 3 cases with Simon-Broome criteria published in PMID: 20538126).

PP3

REVEL: 0,907. Score is above 0,75.

PM2

No population data was found for this allele in gnomAD (gnomAD v2.1.1).

PVS1

Missense variant. Not applicable.

BA1

No population data was found for this allele in gnomAD (gnomAD v2.1.1).

BS2

No unaffected individuals identified with the variant.

BS4

Only one family with non-segregations reported - at least two families are needed.

BS3

No functional study showing non-damaging effect on protein function or splicing.

BS1

No population data was found for this allele in gnomAD (gnomAD v2.1.1).

BP5

Not applicable.

BP7

Missense variant. Not applicable.

BP2

1 case has also APOE c.683G>A;p.(Trp228*) variant and has heterozygous FH phenotype (LDL not above 350mg/dl). Other family members also have the APOE variant (Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge). 2nd variant is not in LDLR, APOB or PCSK9, so BP2 is Not Met at this moment.

BP3

Not applicable.

BP4

REVEL: 0,907. Score is not below 0,15.

BP1

Not applicable.

PS2

No de novo cases were identified.

PS1

No variant described that leads to the same amino acid change.

PP2

Not applicable.

PM6

No de novo cases were identified.

PM3

Not identified in individuals with other variants.

PM1

Missense at codon 441. PM2 is Met, but it is not exon 4 or any of the 60 Cys residues listed. Not applicable.

PM4

Missense variant. Not applicable.

PM5

No other missense variants classified as Pathogenic in the same codon. Two other missense variants described in the same codon (accessed 19 August 2020): (1)NM_000527.5(LDLR):c.1322T>A (p.Ile441Asn) (ClinVar ID 251782) - classified as Likely pathogenic by these guidelines. (2)NM_000527.5(LDLR):c.1323C>G (p.Ile441Met) (ClinVar ID 251784) - classified as VUS by these guidelines.

Approved on: 2021-06-09

Published on: 2021-06-24

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.