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.2017A>C (p.Ser673Arg)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA038161

252172 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 455c0142-2d2a-44ed-ae97-11feb6cdf45f

Approved on: 2025-03-28

Published on: 2025-06-30

HGVS expressions

NM_000527.5:c.2017A>C

NM_000527.5(LDLR):c.2017A>C (p.Ser673Arg)

NC_000019.10:g.11120399A>C

CM000681.2:g.11120399A>C

NC_000019.9:g.11231075A>C

CM000681.1:g.11231075A>C

NC_000019.8:g.11092075A>C

NG_009060.1:g.36019A>C

ENST00000252444.10:c.2275A>C

ENST00000559340.2:c.*86A>C

ENST00000560467.2:c.1897A>C

ENST00000558518.6:c.2017A>C

ENST00000252444.9:c.2271A>C

ENST00000455727.6:c.1513A>C

ENST00000535915.5:c.1894A>C

ENST00000545707.5:c.1606+166A>C

ENST00000557933.5:c.2017A>C

ENST00000558013.5:c.2017A>C

ENST00000558518.5:c.2017A>C

ENST00000559340.1:c.598A>C

NM_000527.4:c.2017A>C

NM_001195798.1:c.2017A>C

NM_001195799.1:c.1894A>C

NM_001195800.1:c.1513A>C

NM_001195803.1:c.1606+166A>C

NM_001195798.2:c.2017A>C

NM_001195799.2:c.1894A>C

NM_001195800.2:c.1513A>C

NM_001195803.2:c.1606+166A>C

Uncertain Significance

PM2

BP4 PS4 PS3 PP3 PM1 PM5 BS3

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.2017A>C (p.Ser673Arg) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence code PM2 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 28 March 2025. The supporting evidence is as follows: PM2: PopMax MAF= 0.0000008474 (0.00008474%) in European non-Finnish exomes + genomes (gnomAD v.4.1.0).

PM2

PopMax MAF= 0.0000008474 (0.00008474%) in European non-Finnish exomes + genomes (gnomAD v.4.1.0).

BP4

REVEL = 0.504, it is not below 0.50.

PS4

Variant meets PM2 and is identified in 1 Brazilian FH index with heterozygous FH following WHO criteria from PMID: 11933210. However, the case harbours two LDLR variants c.2017A>C and c.2088C>G and cis/trans status was not determined.

PS3

No functional study.

PP3

REVEL = 0.504, it is not below 0.50, splicing evaluation required. A) not on limits B) does not create AG C) there is an AG nearby but splicing scores are negative Variant is not predicted to alter splicing.

PM1

Variant meets PM2 but it is not in exon 4 (located in exon 14) and does not alter a critical Cys residue.

PM5

There is another missense variant in same codon NM_000527.5(LDLR):c.2018G>A (p.Ser673Asn), but not classified as Pathogenic by LDLR guidelines.

BS3

No functional study.

Curation History

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