Variant classification summary

NM_000527.5:c.1775G>A

LDLR · NP_000518.1:p.(Gly592Glu) · NM_000527.5

GRCh37: chr19:11227604 G>A · GRCh38: chr19:11116928 G>A

Gene: LDLR Transcript: NM_000527.5

Final call

VUS

PM2 moderate PP3 supporting PP5 supporting

Variant details

Gene

LDLR

Transcript

NM_000527.5

Protein

NP_000518.1:p.(Gly592Glu)

gnomAD AF

4.6470877630406575e-05 (v4.1)

ClinVar

Pathogenic

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 supports pathogenicity at Moderate strength because the gnomAD v4.1 PopMax FAF is 0.00004863.

2

PP3 supports pathogenicity because REVEL is 0.938, above the VCEP threshold of 0.75.

3

PP5 is recorded as Supporting based on an expert-panel ClinVar Pathogenic classification.

4

VUS results because 1 Moderate plus 2 Supporting criteria do not meet an ACMG/AMP 2015 pathogenic rule.

Final determination: Under ACMG/AMP 2015 Table 5, 1 Moderate plus 2 Supporting criteria satisfies no pathogenic or benign rule, so the final call is VUS.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	Not applicable: c.1775G>A is a missense p.(Gly592Glu) substitution, not one of the VCEP-specified null variant classes eligible for PVS1.	cspec pvs1_variant_assessment
PS1	Not assessed	Not assessed: no independently pathogenic alternate-nucleotide variant at codon 592 was identified to satisfy the VCEP's same-amino-acid PS1 rule.	clinvar spliceai
PS2	Not assessed	Not assessed: no patient-specific parental testing, confirmed maternity and paternity, or documented absence of family history is available.	cspec
PS3	Not assessed	Not assessed: the exact variant showed <2% LDLR activity, but cell zygosity and the VCEP-required assay design are not established for strength calibration.	cspec PMID:1301956
PS4	Not assessed	Not assessed: 21 and 38 unrelated cases exceed the >=10 threshold, but validated FH diagnostic criteria are not documented in the available reports.	cspec PMID:11317361 PMID:20145306 gnomad_v4
PM1	Not met	Not met: p.Gly592Glu is in exon 12, whereas LDLR PM1 is restricted to exon 4 or one of 60 conserved cysteine residues.	cspec gnomad_v4
PM2	Met	Met at Moderate: gnomAD v4.1 PopMax FAF is 0.00004863 (0.004863%), below the VCEP's <=0.0002 (0.02%) threshold.	cspec gnomad_v4
PM3	Not assessed	Not assessed: five homozygous observations are reported, but no single additional pathogenic variant and its in-trans phase are documented for the required PM3 configuration.	cspec PMID:11317361 gnomad_v4
PM4	Not met	Not met: c.1775G>A causes a missense substitution, not the VCEP-required in-frame deletion, insertion, or whole-exon duplication, despite PopMax FAF 0.00004863 meeting PM2.	cspec pvs1_variant_assessment gnomad_v4
PM5	Not assessed	Not assessed: no qualifying pathogenic missense comparator at codon 592 was available, and the comparator search was incomplete.	cspec pm5_candidates
PM6	Not assessed	Not assessed: the PS2 de novo pathway cannot be evaluated because patient-specific parental testing and de novo documentation are absent.	cspec
PP1	Not assessed	Not assessed: no family-specific informative meioses or affected relatives with LDL-C above the 75th centile are reported.	cspec PMID:11317361 PMID:1301956 PMID:15864114 PMID:20663204
PP2	N/A	Not applicable: the LDLR VCEP explicitly excludes PP2 for this VCEP.	cspec
PP3	Met	Met at Supporting: REVEL score 0.938 meets the VCEP PP3 missense threshold of >=0.75.	cspec revel
PP4	Not assessed	Not assessed: FH is reported, but validated diagnostic criteria and exclusion of alternative hypercholesterolemia causes are not documented.	cspec PMID:11317361 PMID:20145306 gnomad_v4
PP5	Met	Not applicable: the FH VCEP explicitly excludes PP5, regardless of reported pathogenic classifications.	cspec clinvar
BA1	Not met	Not met: gnomAD v4.1 PopMax FAF is 0.00004863 (0.004863%), below the VCEP's >=0.005 (0.5%) threshold.	cspec gnomad_v4
BS1	Not met	Not met: gnomAD v4.1 PopMax FAF is 0.00004863 (0.004863%), below the VCEP's >=0.002 (0.2%) threshold.	cspec gnomad_v4
BS2	Not assessed	Not assessed: gnomAD reports 2 homozygotes, but their well-phenotyped, untreated, normolipidemic adult status is unavailable.	cspec gnomad_v4
BS3	Not met	Not met: the exact variant had <2% LDLR activity, not the VCEP's >90% or >95% benign whole-cycle activity thresholds.	cspec PMID:1301956
BS4	Not assessed	Not assessed: no two unrelated families with at least two informative meioses and an unaffected carrier below the LDL-C 50th centile are reported.	cspec
BP1	N/A	Not applicable: the LDLR VCEP explicitly excludes BP1 for this VCEP.	cspec
BP2	Not assessed	Not assessed: no qualifying pathogenic partner variant, heterozygous FH phenotype, or in-trans phase is documented for this additional LDLR variant.	cspec
BP3	N/A	Not applicable: the VCEP excludes BP3 for this gene.	cspec
BP4	Not assessed	Not assessed: REVEL 0.938 exceeds the BP4 cutoff of <=0.5, and no governing-rule MaxEntScan result is available.	cspec revel
BP5	N/A	Not applicable: the FH VCEP explicitly excludes BP5 for LDLR interpretation.	cspec
BP6	N/A	Not applicable: the FH VCEP explicitly excludes BP6, regardless of any benign source assertion.	cspec
BP7	N/A	Not applicable: c.1775G>A is missense, producing p.(Gly592Glu), whereas the VCEP BP7 rule requires a synonymous variant.	cspec

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