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.1661C>T (p.Ser554Leu)

CA10585551

251960 (ClinVar)

Gene: LDLR (HGNC:3949)

Condition: hypercholesterolemia, familial (MONDO:0007750)

Inheritance Mode: Semidominant inheritance

UUID: 9b184085-913b-494a-b2a9-9cb690ff1d93

Approved on: 2025-05-09

Published on: 2025-10-08

HGVS expressions

NM_000527.5:c.1661C>T

NM_000527.5(LDLR):c.1661C>T (p.Ser554Leu)

NC_000019.10:g.11116168C>T

CM000681.2:g.11116168C>T

NC_000019.9:g.11226844C>T

CM000681.1:g.11226844C>T

NC_000019.8:g.11087844C>T

NG_009060.1:g.31788C>T

ENST00000252444.10:c.1919C>T

ENST00000559340.2:c.1661C>T

ENST00000560467.2:c.1541C>T

ENST00000558518.6:c.1661C>T

ENST00000252444.9:c.1915C>T

ENST00000455727.6:c.1157C>T

ENST00000535915.5:c.1538C>T

ENST00000545707.5:c.1280C>T

ENST00000557933.5:c.1661C>T

ENST00000558013.5:c.1661C>T

ENST00000558518.5:c.1661C>T

ENST00000559340.1:c.382C>T

NM_000527.4:c.1661C>T

NM_001195798.1:c.1661C>T

NM_001195799.1:c.1538C>T

NM_001195800.1:c.1157C>T

NM_001195803.1:c.1280C>T

NM_001195798.2:c.1661C>T

NM_001195799.2:c.1538C>T

NM_001195800.2:c.1157C>T

NM_001195803.2:c.1280C>T

Uncertain Significance

PP4 PM2 BP4

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

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.1661C>T (p.Ser554Leu) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP4 and BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 9 May 2025. The supporting evidence is as follows: PM2: PopMax MAF = 0.00001098 (0.001098%) in South Asian exomes (gnomAD v4.1.0). PP4: Variant meets PM2 and is identified in at least 1 index case with Possible FH by Simon-Broome criteria from Taiwan (PMID 22353362 (Chiou et al., 2012); PMID 33994402 (Huang et al., 2022)), after alternative causes of high cholesterol were excluded. BP4: REVEL = 0.456, 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 donor and acceptor site, but it does not create AG/GT. The variant is not predicted to alter splicing.

PP4

Variant meets PM2 and is identified in at least 1 index cases who fulfill Simon-Broome criteria of possible FH from Taiwan (PMID: 22353362; PMID: 33994402), after alternative causes of high cholesterol were excluded, so PP4 is met.

PM2

PopMax MAF = 0.00001098 (0.001098%) in South Asian exomes (gnomAD v4.1.0), so PM2 is met.

BP4

REVEL = 0.456, 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 donor and acceptor site, but it does not create AG/GT Variant is not predicted to alter splicing, so BP4 is 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 fulfill Simon-Broome criteria of possible FH from Taiwan (PMID: 22353362; PMID: 33994402), after alternative causes of high cholesterol were excluded, so PS4 is Not Met.

PS1

No more missense variants that lead to the same amino acid change, so PS1 is Not Met.

PS3

There are no functional studies reported for this variant, so BS3 is Not Met.

BA1

PopMax MAF = 0.00001098 (0.001098%) in population exomes (gnomAD v4.1.0), so BA1 is Not Met.

PP1

Segregation data not reported, so PP1 is Not Met.

PP3

REVEL = 0.456, it is below 0.50, splicing evaluation required. Functional data on splicing not available. A) 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, but there is no AG/GT nearby Variant is not predicted to alter splicing, so PP3 is Not Met.

PM3

Not observed in trans with other LP/P variants, so PM3 is Not Met.

PM5

1 other missense variant in the same codon: - NM_000527.5(LDLR):c.1661C>G (p.Ser554Trp) (ClinVar ID: 3231953) - Uncertain significance by these guidelines There is no variant in the same codon classified as Pathogenic by these guidelines, so PM5 is Not Met.

PM1

Variant meets PM2 but is not located in exon 4 or alters a cysteine residue, so PM1 is Not Met.

PM4

Variant meets PM2 and is missense, so PM4 is Not Met.

PM6

de novo occurrence data not reported, so PM6 is Not Met.

BS4

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

BS3

There are no functional studies reported for this variant, so BS3 is Not Met.

BS1

PopMax MAF = 0.00001098 (0.001098%) in population exomes (gnomAD v4.1.0), so BS1 is Not Met.

BS2

Case-control data not reported, so BS2 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.

PVS1

Variant is missense, so PVS1 is Not Met.

Curation History

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.