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.1447T>C (p.Trp483Arg)

CA10585457

251847 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 0db8711c-7233-4fac-93bc-9e2eee4954ab

Approved on: 2023-04-29

Published on: 2023-04-29

HGVS expressions

NM_000527.5:c.1447T>C

NM_000527.5(LDLR):c.1447T>C (p.Trp483Arg)

NC_000019.10:g.11113623T>C

CM000681.2:g.11113623T>C

NC_000019.9:g.11224299T>C

CM000681.1:g.11224299T>C

NC_000019.8:g.11085299T>C

NG_009060.1:g.29243T>C

ENST00000558518.6:c.1447T>C

ENST00000252444.9:n.1701T>C

ENST00000455727.6:c.943T>C

ENST00000535915.5:c.1324T>C

ENST00000545707.5:c.1066T>C

ENST00000557933.5:c.1447T>C

ENST00000558013.5:c.1447T>C

ENST00000558518.5:c.1447T>C

ENST00000559340.1:n.168T>C

ENST00000560467.1:n.927T>C

NM_000527.4:c.1447T>C

NM_001195798.1:c.1447T>C

NM_001195799.1:c.1324T>C

NM_001195800.1:c.943T>C

NM_001195803.1:c.1066T>C

NM_001195798.2:c.1447T>C

NM_001195799.2:c.1324T>C

NM_001195800.2:c.943T>C

NM_001195803.2:c.1066T>C

Uncertain Significance

PS4_Supporting PP4 PP3 PM2

BP7 BP2 BP4 PVS1 PS1 PS2 PS3 BA1 PP1 PM1 PM3 PM5 PM4 PM6 BS4 BS3 BS1 BS2

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.1447T>C (p.Trp483Arg) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PP4, PS4_Supporting) 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 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is Met. PP3 - REVEL = 0.914. It is above 0.75, so PP3 is Met. PS4_Supporting - Variant meets PM2 and is identified in 5 unrelated index cases (1 index case with Simon-Broome/DLCN criteria of definite FH (LDL=12,4 mmol/L and tendinous xanthomas) from Ireland (PMID 8535447); 3 index case with Simon-Broome criteria of possible FH from UK (PMID 17539906); 1 index case with FH criteria (LDL-C >95th percentile and AD inheritance pattern of hypercholesterolemia and a family history of hypercholesterolemia and cardiovascular disease) from The Netherlands (PMID 21382890), so PS4_Supporting is met. PP4 - Variant meets PM2 and is identified in at least one index case who fulills clinical criteria for FH (see PS4 for details), after alternative causes of high cholesterol were excluded.

PS4_Supporting

Variant meets PM2 and is identified in 5 unrelated index cases (1 index case with Simon-Broome/DLCN criteria of definite FH (LDL=12,4 mmol/L and tendinous xanthomas) from Ireland (PMID 8535447); 3 index case with Simon-Broome criteria of possible FH from UK (PMID 17539906); 1 index case with FH criteria (LDL-C >95th percentile and AD inheritance pattern of hypercholesterolemia and a family history of hypercholesterolemia and cardiovascular disease) from The Netherlands (PMID 21382890), so PS4_Supporting is met.

PP4

Variant meets PM2 and is identified in at least one index case who fulfills clinical criteria for FH (see PS4 for details), after alternative causes of high cholesterol were excluded.

PP3

REVEL = 0.914. It is above 0.75, so PP3 is Met.

PM2

This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is Met.

BP7

Variant is not synonymous, so BP7 is Not Met.

BP2

Not observed in trans with other LP/P variants, so BP2 is Not Met.

BP4

REVEL = 0.914. It is not below 0.50, so BP4 is Not Met.

PVS1

Variant is missense, so PVS1 is Not Met.

PS1

No more missense variants that lead to the same amino acid change, so PS1 is Not Met.

PS2

de novo occurrence data not reported, so PS2 is Not Met.

PS3

There are no functional studies reported for this variant, so PS3 is not met.

BA1

This variant is absent from gnomAD (gnomAD v2.1.1), so BA1 is not met.

PP1

Segregation data without phenotype reported (six affected family members were tested and shown to have W462R in PMID: 8535447), so PP1 is Not Met.

PM1

Variant meets PM2 but is not located in exon 4 or alters a cysteine residues, so PM1 is Not Met.

PM3

Not observed in trans with other LP/P variants, so PM3 is Not Met.

PM5

3 other missense variants in the same codon: - NM_000527.5(LDLR):c.1449G>T (p.Trp483Cys) (ClinVar ID 251850) - VUS by these guidelines - NNM_000527.5(LDLR):c.1448G>T (p.Trp483Leu) (ClinVar ID 440645) - VUS by these guidelines - NM_000527.5(LDLR):c.1449G>C (p.Trp483Cys) (ClinVar ID 440646) - VUS by these guidelines There are no more variants in the same codon classified as Pathogenic by these guidelines, so PM5 is not met.

PM4

Variant meets PM2 and is missense, so PM4 is Not Met.

PM6

de novo occurrence data not reported, so PM6 is Not Met.

BS4

Lack of segregation data not reported, so BS4 is Not Met.

BS3

There are no functional studies reported for this variant, so BS3 is not met.

BS1

This variant is absent from gnomAD (gnomAD v2.1.1), so BS1 is not met.

BS2

Not detected in 100 normal chromosomes (PMID 8535447), so BS2 is not met.

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