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.1942T>G (p.Ser648Ala)

CA404093067

431538 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: bb46808e-320f-4871-85e6-2d43832b3dc6

HGVS expressions

NM_000527.5:c.1942T>G

NM_000527.5(LDLR):c.1942T>G (p.Ser648Ala)

NC_000019.10:g.11120188T>G

CM000681.2:g.11120188T>G

NC_000019.9:g.11230864T>G

CM000681.1:g.11230864T>G

NC_000019.8:g.11091864T>G

NG_009060.1:g.35808T>G

ENST00000558518.6:c.1942T>G

ENST00000252444.9:n.2196T>G

ENST00000455727.6:c.1438T>G

ENST00000535915.5:c.1819T>G

ENST00000545707.5:c.1561T>G

ENST00000557933.5:c.1942T>G

ENST00000558013.5:c.1942T>G

ENST00000558518.5:c.1942T>G

ENST00000559340.1:n.523T>G

NM_000527.4:c.1942T>G

NM_001195798.1:c.1942T>G

NM_001195799.1:c.1819T>G

NM_001195800.1:c.1438T>G

NM_001195803.1:c.1561T>G

NM_001195798.2:c.1942T>G

NM_001195799.2:c.1819T>G

NM_001195800.2:c.1438T>G

NM_001195803.2:c.1561T>G

Uncertain Significance

BP4 PM2

PVS1 BS2 BS4 BS3 BS1 BP7 BP2 PS1 PS2 PS4 PS3 BA1 PP4 PP1 PP3 PM6 PM1 PM5 PM3 PM4

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>G (p.Ser648Ala) variant is classified as Uncertain significance - insufficient evidencefor Familial Hypercholesterolemia by applying evidence codes (PM2 and BP4) 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 MAF = 0.0001602 (0.01602%) in African/African American exomes+genomes (gnomAD v2.1.1), so PM2 is met. BP4 - REVEL = 0.487, it is below 0.50, splicing evaluation 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. --- BP4 is Met.

BP4

REVEL = 0.487, it is below 0.50, splicing evaluation 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. --- BP4 is Met.

PM2

PopMax MAF = 0.0001602 (0.01602%) in African/African American exomes+genomes (gnomAD v2.1.1), so PM2 is met.

PVS1

Variant is missense, so PVS1 is Not Met.

BS2

No control individuals tested, so BS2 is Not Met.

BS4

Variant does not segregate with FH phenotype in only 1 informative meiosis from 1 family (minimum 2) from Laboratory of Genetics and Molecular Cardiology, so BS4 is not met.

BS3

There are no functional studies reported for this variant, so BS3 is not met.

BS1

FAF = 0.00009372 (0.009372%) in african/african american genomes (gnomAD v2.1.1), so BS1 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.

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, but data reported does not meet any validated criteria, so PS4 is Not Met.

PS3

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

BA1

FAF = 0.00009372 (0.009372%) in african/african american genomes (gnomAD v2.1.1), so BA1 is not met.

PP4

Variant meets PM2, but data reported does not meet any validated criteria, so PP4 is Not Met.

PP1

Variant segregates with FH phenotype in only 1 informative meiosis (minimum 2) from 1 family from Laboratory of Genetics and Molecular Cardiology, so PP1 is not met.

PP3

REVEL = 0.487, 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.

PM5

2 other missense variants in the same codon: - NM_000527.5(LDLR):c.1943C>T (p.Ser648Phe) (ClinVar ID 440670) - VUS by these guidelines - NM_000527.5(LDLR):c.1942T>C (p.Ser648Pro) (ClinVar ID 252120) - Likely Pathogenic by these guidelines No more missense variants at the same codon, classified as Pathogenic, so PM5 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.

Approved on: 2023-01-27

Published on: 2023-04-01

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