Evidence Repository - GenboreeKB

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.1327T>C (p.Trp443Arg)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA033596

998052 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 49662f67-017a-43b6-904e-709de915230e

Approved on: 2025-01-31

Published on: 2025-02-03

HGVS expressions

NM_000527.5:c.1327T>C

NM_000527.5(LDLR):c.1327T>C (p.Trp443Arg)

NC_000019.10:g.11113418T>C

CM000681.2:g.11113418T>C

NC_000019.9:g.11224094T>C

CM000681.1:g.11224094T>C

NC_000019.8:g.11085094T>C

NG_009060.1:g.29038T>C

ENST00000252444.10:c.1585T>C

ENST00000559340.2:c.1327T>C

ENST00000560467.2:c.1207T>C

ENST00000558518.6:c.1327T>C

ENST00000252444.9:c.1581T>C

ENST00000455727.6:c.823T>C

ENST00000535915.5:c.1204T>C

ENST00000545707.5:c.946T>C

ENST00000557933.5:c.1327T>C

ENST00000558013.5:c.1327T>C

ENST00000558518.5:c.1327T>C

ENST00000559340.1:c.48T>C

ENST00000560173.1:n.326T>C

ENST00000560467.1:c.807T>C

NM_000527.4:c.1327T>C

NM_001195798.1:c.1327T>C

NM_001195799.1:c.1204T>C

NM_001195800.1:c.823T>C

NM_001195803.1:c.946T>C

NM_001195798.2:c.1327T>C

NM_001195799.2:c.1204T>C

NM_001195800.2:c.823T>C

NM_001195803.2:c.946T>C

Likely Pathogenic

PM3 PM5 PM2 PP3 PP4 PS4_Supporting

PP1

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.1327T>C (p.Trp443Arg) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PM3, PM5, PP3, PP4 and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 31 January 2025. The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v4.1.0). PP3: REVEL = 0.951. PM5: 1 other missense variant in the same codon: NM_000527.5(LDLR):c.1329G>C (p.Trp443Cys) (ClinVar ID 251792)- Pathogenic by these guidelines. PS4_Supporting, PP4: Variant meets PM2 and is identified in at least 4 unrelated index cases who fulfill criteria for FH: 1 patient with DLCN >=6 from PMID 28458923 (Korneva et al., 2017), Russia; 1 patient with DLCN >=6 from PMID 32423031 (Semenova et al., 2020), Russia; 2 patients with DLCN >=6 from PMID 33418990 (Meshkov et al., 2021), Russia. PM3: Variant meets PM2 and is identified in an index case with homozygous FH phenotype (treated LDL-C > 15.2 mmol/L). This patient also carries the c.2141-954_2390-318del variant, classified as Likely Pathogenic by these guidelines, in trans (PMID 36901902, Nazarenko et al., 2023).

PM3

Variant meets PM2 and is identified in an index case with homozygous FH phenotype (treated LDL-C > 15.2 mmol/L). This patient also carries the c.2141-954_2390-318del variant, classified as Likely Pathogenic by these guidelines, in trans (PMID: 36901902).

PM5

1 other missense variant in the same codon: - NM_000527.5(LDLR):c.1329G>C (p.Trp443Cys) variant (ClinVar ID 251792) - Pathogenic by these guidelines There is 1 variant in the same codon classified as Pathogenic by these guidelines.

PM2

This variant is absent from gnomAD (gnomAD v4.1.0).

PP3

REVEL = 0.951

PP4

Variant meets PM2 and is identified in at least 1 index case who fulfills DLCN>=6 criteria for FH after alternative causes of high cholesterol were excluded (PMID: 28458923).

PS4_Supporting

Variant meets PM2 and is identified in at least 4 unrelated index cases who fulfill SB definite FH or DLCN>=6: (1): PMID 28458923- 1 FH patient carrying variant who meets definite FH criteria (2): PMID 32423031- 1 unrelated FH patient carrying variant who meets DLCN>6 criteria (3): PMID 33418990- 2 unrelated FH patient carrying variant who meets DLCN>6 criteria

PP1

PMID 28458923 - table states 1 family with 3 patients, but gave no data.

Curation History

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