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.1942T>C (p.Ser648Pro)

CA10585687

252120 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 5486373f-4e03-4ac7-b53e-fce531d34ddf

Approved on: 2023-04-28

Published on: 2023-05-01

HGVS expressions

NM_000527.5:c.1942T>C

NM_000527.5(LDLR):c.1942T>C (p.Ser648Pro)

NC_000019.10:g.11120188T>C

CM000681.2:g.11120188T>C

NC_000019.9:g.11230864T>C

CM000681.1:g.11230864T>C

NC_000019.8:g.11091864T>C

NG_009060.1:g.35808T>C

ENST00000558518.6:c.1942T>C

ENST00000252444.9:n.2196T>C

ENST00000455727.6:c.1438T>C

ENST00000535915.5:c.1819T>C

ENST00000545707.5:c.1561T>C

ENST00000557933.5:c.1942T>C

ENST00000558013.5:c.1942T>C

ENST00000558518.5:c.1942T>C

ENST00000559340.1:n.523T>C

NM_000527.4:c.1942T>C

NM_001195798.1:c.1942T>C

NM_001195799.1:c.1819T>C

NM_001195800.1:c.1438T>C

NM_001195803.1:c.1561T>C

NM_001195798.2:c.1942T>C

NM_001195799.2:c.1819T>C

NM_001195800.2:c.1438T>C

NM_001195803.2:c.1561T>C

Likely Pathogenic

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Insufficient Evidence"

PS3 PP4 PM2

PVS1 BP7 BP2 BP4 PS1 PS2 PS4 PP1 PP3 PM6 PM1 PM3 PM4 PM5 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

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

The NM_000527.5(LDLR):c.1942T>C (p.Ser648Pro) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PS3, PM2 and PP4) 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: PS3 - 2 Level 1 assays: PMID 25386756: Heterologous cells (CHO), FACS assays - result - 50% cell surface LDLR and binding and 26% uptake. PMID 23021490: Heterologous cells (CHO), 125I-LDL and WB assays - result - 30-50% LDLR activity; reduced mature protein. ---- activity is below 70% of wild-type, so functional studies are consistent with damaging effect and PS3 is Met. PM2 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is Met. PP4 - Variant meets PM2 and is identified in 1 index cases who fulfills SB possible criteria for FH from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge, so PP4 is met.

PS3

2 Level 1 assays: PMID 25386756: Heterologous cells (CHO), FACS assays - result - 50% cell surface LDLR and binding and 26% uptake. PMID 23021490: Heterologous cells (CHO), 125I-LDL and WB assays - result - 30-50% LDLR activity; reduced mature protein. ---- activity is below 70% of wild-type, so functional studies are consistent with damaging effect and PS3 is Met.

PP4

Variant meets PM2 and is identified in 1 index cases who fulfills SB possible criteria for FH from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge, so PP4 is met.

PM2

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

PVS1

Variant is missense, so PVS1 is Not 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 = 0.604. It is not below 0.50, so BP4 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.

PS4

Variant meets PM2 and is identified in only 1 index cases who fulfills SB possible criteria for FH from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge, so PS4 is not met.

PP1

Segregation data not reported, so PP1 is Not Met.

PP3

REVEL = 0.604, it is not above 0.75, so splicing evaluation is required. 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) variant is exonic and there is no GT nearby Variant is not predicted to alter splicing --- PP3 is not met.

PM6

de novo occurrence data not reported, so PM6 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

2 other missense variants in the same codon: - NM_000527.5(LDLR):c.1942T>G (p.Ser648Ala) (ClinVar ID 431538) - VUS by these guidelines - NM_000527.5(LDLR):c.1943C>T (p.Ser648Phe) (ClinVar ID 440670) - VUS by these guidelines No more missense variants at the same codon, classified as Pathogenic, so PM5 is Not Met.

BA1

No population data was found for this variant in gnomAD (gnomAD v2.1.1), so BA1 is Not Met.

BS2

Not observed in 100 normolipidemic individuals from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge, so BS2 is Not Met.

BS4

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

BS3

BS1

No population data was found for this variant in gnomAD (gnomAD v2.1.1), so BS1 is Not Met.

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