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.1906G>A (p.Gly636Ser)

CA037376

252109 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 2b7bdac1-0590-477b-83aa-348c94c2047f

HGVS expressions

NM_000527.5:c.1906G>A

NM_000527.5(LDLR):c.1906G>A (p.Gly636Ser)

NC_000019.10:g.11120152G>A

CM000681.2:g.11120152G>A

NC_000019.9:g.11230828G>A

CM000681.1:g.11230828G>A

NC_000019.8:g.11091828G>A

NG_009060.1:g.35772G>A

ENST00000558518.6:c.1906G>A

ENST00000252444.9:n.2160G>A

ENST00000455727.6:c.1402G>A

ENST00000535915.5:c.1783G>A

ENST00000545707.5:c.1525G>A

ENST00000557933.5:c.1906G>A

ENST00000558013.5:c.1906G>A

ENST00000558518.5:c.1906G>A

ENST00000559340.1:n.487G>A

NM_000527.4:c.1906G>A

NM_001195798.1:c.1906G>A

NM_001195799.1:c.1783G>A

NM_001195800.1:c.1402G>A

NM_001195803.1:c.1525G>A

NM_001195798.2:c.1906G>A

NM_001195799.2:c.1783G>A

NM_001195800.2:c.1402G>A

NM_001195803.2:c.1525G>A

Uncertain Significance

PM2 PP3

PS1 PS2 PS3 PS4 PM1 PM3 PM4 PM5 PM6 BA1 PVS1 BP7 BP4 BP2 BS4 BS3 BS1 BS2 PP1 PP4

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 1.1

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

The NM_000527.5(LDLR):c.1906G>A (p.Gly636Ser) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PM2 - PopMax MAF = 0.00009643 (0.009643%) in Ashkenazi Jewish exomes+genomes (gnomAD v2.1.1), so PM2 is Met. PP3 - REVEL = 0.95. It is above 0.75, so PP3 is Met.

PM2

PopMax MAF = 0.00009643 (0.009643%) in Ashkenazi Jewish exomes+genomes (gnomAD v2.1.1), so PM2 is Met.

PP3

REVEL = 0.95. It is above 0.75, so PP3 is 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.

PS3

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

PS4

Variant meets PM2, but data reported does not meet any validated criteria, so PS4 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

Observed in an index case (phenotype not reported) with LDLR c.313+2T>C, classified as Pathogenic by these guidelines, but cannot determine if the variants are in trans, so PM3 is Not Met.

PM4

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

PM5

2 other missense variant(s) in the same codon: - NM_000527.5(LDLR):c.1907G>T (p.Gly636Val) (ClinVar ID: 438327) - VUS by these guidelines - NM_000527.5(LDLR):c.1907G>A (p.Gly636Asp) (ClinVar ID: 252110) - VUS by these guidelines There are no variants in the same codon classified as Pathogenic by these guidelines, so PM5 is not met.

PM6

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

BA1

FAF = 0.000007952 (0.0007952%) in Ashkenazi Jewish + European (Non-Finnish) exomes (gnomAD v2.1.1), so BA1 is not met.

PVS1

Variant is missense, so PVS1 is Not Met.

BP7

Variant is not synonymous, so BP7 is Not Met.

BP4

REVEL = 0.95. It is not below 0.50, so BP4 is Not Met.

BP2

Observed in an index case (phenotype not reported) with LDLR c.313+2T>C, classified as Pathogenic by these guidelines, but cannot determine if the variants are in trans, so BP2 is Not Met.

BS4

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

FAF = 0.000007952 (0.0007952%) in aAshkenazi Jewish + European (Non-Finnish) exomes (gnomAD v2.1.1), so BS1 is not met.

BS2

No control individuals tested, so BS2 is Not Met.

PP1

Segregation data not reported, so PP1 is Not Met.

PP4

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

Approved on: 2022-08-29

Published on: 2022-12-23

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