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.1927G>C (p.Ala643Pro)

CA10585682

252114 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 67ec196b-6313-43ac-a7da-0017f218f6af

Approved on: 2024-07-02

Published on: 2024-09-09

HGVS expressions

NM_000527.5:c.1927G>C

NM_000527.5(LDLR):c.1927G>C (p.Ala643Pro)

NC_000019.10:g.11120173G>C

CM000681.2:g.11120173G>C

NC_000019.9:g.11230849G>C

CM000681.1:g.11230849G>C

NC_000019.8:g.11091849G>C

NG_009060.1:g.35793G>C

ENST00000252444.10:c.2185G>C

ENST00000559340.2:c.1787G>C

ENST00000560467.2:c.1807G>C

ENST00000558518.6:c.1927G>C

ENST00000252444.9:c.2181G>C

ENST00000455727.6:c.1423G>C

ENST00000535915.5:c.1804G>C

ENST00000545707.5:c.1546G>C

ENST00000557933.5:c.1927G>C

ENST00000558013.5:c.1927G>C

ENST00000558518.5:c.1927G>C

ENST00000559340.1:c.508G>C

NM_000527.4:c.1927G>C

NM_001195798.1:c.1927G>C

NM_001195799.1:c.1804G>C

NM_001195800.1:c.1423G>C

NM_001195803.1:c.1546G>C

NM_001195798.2:c.1927G>C

NM_001195799.2:c.1804G>C

NM_001195800.2:c.1423G>C

NM_001195803.2:c.1546G>C

Uncertain Significance

PP4 PM2

PP3 PM5

Evidence Links 0

Expert Panel

Familial Hypercholesterolemia VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

The NM_000527.5(LDLR):c.1927G>C (p.Ala643Pro) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes 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) on 2 July 2024. The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v2.1.1). PP4: Variant meets PM2 and is identified in at least 1 index case who fulfills Simon Broome criteria for FH (PMID 17539906) after alternative causes of high cholesterol were excluded.

PP4

Variant meets PM2 and is identified in at least 1 index case who fulfills SB possible or definite FH criteria (PMID: 17539906) after alternative causes of high cholesterol were excluded.

PM2

This variant is absent from gnomAD (gnomAD v2.1.1).

PP3

REVEL = 0.686 Does not meet BP4 or PP3 criteria, splicing evaluation required A). Not on limits B). Does not create AG or GT C). There is a GT nearby MES Scores: >var cryptic CTTGTTGCC MAXENT: -25.74 >WT cryptic CTTGTTGGC MAXENT: -14.01 variant cryptic/wild-type cryptic score = -25.74/-14.01 = 1.84 --> it is above 1.1, "I agree with VUS classification, but PP3 not met. I have a general comment on splicing evaluation:Strictly speaking, evaluation of this variant according to the LDLR guidelines is correct. However, there is a general problem with evaluation of two splice sites where at least one has negative MES score. When both splice sites have negative MES score, the resulting ratio (-25.74/-14.01=1.84) suggests that there is an increase in relative strengths between these two cryptic splice sites. However, this is misleading as donor with MES of -25.74 is weaker than -14.01 because the former has a smaller number value. Additionally, negative MES score generally suggests a splice site that is unlikely to be used as a bona fide splice site (though there might be some exceptions). In cases like these I would suggest not using ratio and just generally assume that if the variant cryptic splice site has a negative MES score it will not be used and therefore can be evaluated as having no impact on splicing. Similar situation can arise if wild type cryptic site is negative and variant cryptic site is positive. The resulting ratio will be negative and would be considered below threshold according to the guidelines. However, this is opposite to the real situation as we know that going from negative MES score to positive means relative strength improvement. In this case I would suggest calculating ratio variant cryptic/authentic. In general, this is a problem with scaling systems that traverse the 0. In conclusion, c.1927G>C should not be considered splicing affecting and therefore does not meet PP3. "

PM5

The NM_000527.5(LDLR):c.1928C>T (p.Ala643Val) is classified as VUS by the FH VCEP guidelines.

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