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]

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

CA10576326

226382 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

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

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

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

PP4 PP1_Strong PS4_Supporting PM2

BP4 PS3 PS1 PP3 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

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 follows: PM2: PopMax = 0.00005 in East Asians (gnomAD v2.1.1). PS4_Supporting: Variant meets PM2 and is identified in at least 2 unrelated index cases who fulfil clinical criteria for FH: 1 patient with DLCN >6 from the Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA, Australia; VCI); 1 patient with Simon Broome = Definite FH (PMID: 20236128). PP1_Strong: Variant segregates with the FH phenotype in 8 informative meioses from 1 family from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA, Australia; VCI): 5 affected family members have the variant and 3 non-affected family members do not have the variant. PP4: Variant meets PM2 and is identified in at least 1 index case who fulfills clinical criteria for FH (Cardiovascular Genetics Laboratory - PathWest Laboratory Medicine WA, Australia; VCI), after alternative causes of high cholesterol were excluded.

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).

PP1_Strong

PP1_Strong : Variant segregates with FH phenotype in 8 informative meiosis from 1 family (5 relatives with the phenotype and the variant and 3 relatives without the phenotype and without the variant ) from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA), so PP1_strong is met

PS4_Supporting

4 index cases with clinical criteria of FH: 1 from the Cardiovascular Genetics Laboratory - PathWest Laboratory Medicine WA - with DLCN>6, 1 from PMID: 20236128 with Simon-Broome criteria of definite FH, 1 from Ambry Genetics with DLCN = 8, and 1 from PMID:31993549 with Simon-Broome criteria of possible FH. PMID:20829525, PMID:22883975 and PMID: 28964736 were not considered because of 3 carriers with FH did not fulfil FH clinical criteria

PM2

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

BP4

REVEL score is 0.588

PS3

no functional data available

PS1

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

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

Approved on: 2023-10-25

Published on: 2023-10-25

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