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.1955T>C (p.Met652Thr)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA10576326

226382 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 7dfb2299-5dd6-4bd2-800b-7353722033a5

Approved on: 2022-08-29

Published on: 2022-12-23

HGVS expressions

NM_000527.5:c.1955T>C

NM_000527.5(LDLR):c.1955T>C (p.Met652Thr)

NC_000019.10:g.11120201T>C

CM000681.2:g.11120201T>C

NC_000019.9:g.11230877T>C

CM000681.1:g.11230877T>C

NC_000019.8:g.11091877T>C

NG_009060.1:g.35821T>C

ENST00000252444.10:c.2213T>C

ENST00000559340.2:c.*24T>C

ENST00000560467.2:c.1835T>C

ENST00000558518.6:c.1955T>C

ENST00000252444.9:c.2209T>C

ENST00000455727.6:c.1451T>C

ENST00000535915.5:c.1832T>C

ENST00000545707.5:c.1574T>C

ENST00000557933.5:c.1955T>C

ENST00000558013.5:c.1955T>C

ENST00000558518.5:c.1955T>C

ENST00000559340.1:c.536T>C

NM_000527.4:c.1955T>C

NM_001195798.1:c.1955T>C

NM_001195799.1:c.1832T>C

NM_001195800.1:c.1451T>C

NM_001195803.1:c.1574T>C

NM_001195798.2:c.1955T>C

NM_001195799.2:c.1832T>C

NM_001195800.2:c.1451T>C

NM_001195803.2:c.1574T>C

Likely Pathogenic

PP1_Strong PP4 PM2 PS4_Supporting

PS1 PS3 PP3 PM5 BP4

Evidence Links 0

Expert Panel

Familial Hypercholesterolemia VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

The NM_000527.5(LDLR):c.1955T>C (p.Met652Thr) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PP4, PP1_Moderate and 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 follow: PM2_ Met : Allele frequency is 0.00005 (18394 alleles) in the East Asian subpopulation in GnomAD (gnomAD v2.1.1). PP4_Met : 2 patients with definite FH (1 from the Cardiovascular Genetics Laboratory - PathWest Laboratory Medicine WA - as defined by DLCN>6 and 1 from PMID: 20236128 as defined by Simon Broome score = definite). PS4_Supporting: 2 patients with definite FH (1 from the Cardiovascular Genetics Laboratory - PathWest Laboratory Medicine WA -with DLCN>6 and 1 from PMID: 20236128 with Simon Broome score = definite) and 1 case with untreated LDL-C=348 (Ambry Genetics). PMID:20829525 1 carrier was identified but the FH phenotype was evaluated only considering total and LDL-cholesterol levels above the 95 th percentile when compared with a sex- and age-matched French population. I will not consider this patient. PMID:22883975 1 carrier with clinical FH defined by DLCN score was reported. However, it is impossible to understand if the patient carrying the variant has a DLCN>6. I will not consider this patient. PMID: 28964736 1 carrier with clinical FH was reported in the cohort of ALTERNATIVE study which did not have a recorded diagnosis of FH, as they had very high baseline LDL-C levels (>5.0 mmol/L, ∼193 mg/dL).No data on FH its FC classification is reported. I will not consider this patient. PP1_Strong : Variant segregates with phenotype in 5 relatives in 1 family. (8 informative meiosis)

PP1_Strong

Variant segregates with phenotype in 5 relatives in 1 family. (8 informative meiosis)

PP4

2 patients with definite FH (1 from the Cardiovascular Genetics Laboratory - PathWest Laboratory Medicine WA - as defined by DLCN>6 and 1 from PMID: 20236128 as defined by Simon Broome score = definite).

PM2

Allele frequency is 0.00005 (18394 alleles) in the East Asian subpopulation in GnomAD (gnomAD v2.1.1).

PS4_Supporting

2 patients with definite FH (1 from the Cardiovascular Genetics Laboratory - PathWest Laboratory Medicine WA -with DLCN>6 and 1 from PMID: 20236128 with Simon Broome score = definite) and 1 case with untreated LDL-C=348 (Ambry Genetics). PMID:20829525 1 carrier was identified but the FH phenotype was evaluated only considering total and LDL-cholesterol levels above the 95 th percentile when compared with a sex- and age-matched French population. I will not consider this patient. PMID:22883975 1 carrier with clinical FH defined by DLCN score was reported. However, it is impossible to understand if the patient carrying the variant has a DLCN>6. I will not consider this patient. PMID: 28964736 1 carrier with clinical FH was reported in the cohort of ALTERNATIVE study which did not have a recorded diagnosis of FH, as they had very high baseline LDL-C levels (>5.0 mmol/L, ∼193 mg/dL).No data on FH its FC classification is reported. I will not consider this patient.

PS1

2 variants were found in the same codon but led to different aa change

PS3

no functional data available

PP3

REVEL score is 0.588

PM5

2 variants were found in the same codon leading to a different aa change. However, all these variants were classified as VUS by these guidelines

BP4

REVEL score is 0.588

Curation History

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