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.1975A>C (p.Thr659Pro)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA037634

252140 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 9a4d98e9-5d76-4b32-9b73-d49180628bf2

Approved on: 2023-05-15

Published on: 2025-02-13

HGVS expressions

NM_000527.5:c.1975A>C

NM_000527.5(LDLR):c.1975A>C (p.Thr659Pro)

NC_000019.10:g.11120221A>C

CM000681.2:g.11120221A>C

NC_000019.9:g.11230897A>C

CM000681.1:g.11230897A>C

NC_000019.8:g.11091897A>C

NG_009060.1:g.35841A>C

ENST00000252444.10:c.2233A>C

ENST00000559340.2:c.*44A>C

ENST00000560467.2:c.1855A>C

ENST00000558518.6:c.1975A>C

ENST00000252444.9:c.2229A>C

ENST00000455727.6:c.1471A>C

ENST00000535915.5:c.1852A>C

ENST00000545707.5:c.1594A>C

ENST00000557933.5:c.1975A>C

ENST00000558013.5:c.1975A>C

ENST00000558518.5:c.1975A>C

ENST00000559340.1:c.556A>C

NM_000527.4:c.1975A>C

NM_001195798.1:c.1975A>C

NM_001195799.1:c.1852A>C

NM_001195800.1:c.1471A>C

NM_001195803.1:c.1594A>C

NM_001195798.2:c.1975A>C

NM_001195799.2:c.1852A>C

NM_001195800.2:c.1471A>C

NM_001195803.2:c.1594A>C

Likely Pathogenic

PP4 PM2 PS4_Supporting PP1_Strong

BP2 BP4 BP7 PS2 PS1 PS3 PVS1 PP3 PM1 PM3 PM4 PM5 PM6 BA1 BS2 BS4 BS3 BS1

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

PDF

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

The NM_000527.5(LDLR):c.1975A>C (p.Thr659Pro) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PP1_Strong, PM2, PS4_Supporting and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 15 May 2023. The supporting evidence is as follows: PM2: PopMax MAF = 0.0001853 (0.01853%) in European (Finnish) exomes (gnomAD v2.1.1). PS4_Supporting, PP4: Variant meets PM2 and is identified in 4 unrelated index cases with criteria for FH (TC and LDL >95th percentile and autosomal dominant transmission of hypercholesterolemia in the family) from France (PMID 20809525, Marduel et al. 2010). PP1_Strong: Variant segregates with FH phenotype in at least 6 informative meioses from 3 families from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière, France: 6 affected family members have the variant.

PP4

PM2

PopMax MAF = 0.0001853 (0.01853%) in European (Finnish) exomes (gnomAD v2.1.1), so PM2 is Met.

PS4_Supporting

Variant meets PM2 and is identified in 4 unrelated index cases with criteria for FH (TC and LDL >95th percentile and autosomal dominant transmission of hypercholesterolemia in the family) from France (PMID: 20809525), that possibly are the same 4 index cases with DLCN>6 from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière), so give PS4_Supporting to be conservative.

PP1_Strong

Variant segregates with FH phenotype in at least 6 informative meioses from 3 families from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière): 6 affected family members have the variant.

BP2

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

BP4

REVEL = 0.652. It is not below 0.50, so BP4 is Not Met.

BP7

Variant is not synonymous, so BP7 is Not Met.

PS2

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

PS1

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

PS3

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

PVS1

Variant is missense, so PVS1 is Not Met.

PP3

REVEL = 0.652 It is not above 0.75, splicing evaluation needed. Functional data on splicing not available. A) variant not on limits. B) variant is exonic and at least 50bp downstream from the canonical acceptor site, but it does not create GT. C) there is no a GT nearby. --- PP3 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.

PM4

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

PM5

1 other missense variant in the same codon: - NM_000527.5(LDLR):c.1976C>A (p.Thr659Asn) (ClinVar ID 252141) - Uncertain significance - insufficient evidence by these guidelines There are no more variants in the same codon classified as Pathogenic by these guidelines, so PM5 is Not Met.

PM6

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

BA1

FAF = 0.00001686 (0.001686%) in European (non-Finnish) exomes (gnomAD v2.1.1), so BA1 is not met.

BS2

Case-control data not reported, so BS2 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

FAF = 0.00001686 (0.001686%) in European (non-Finnish) exomes (gnomAD v2.1.1), so BS1 is not met.

Curation History

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