Variant classification summary

NM_000527.5:c.621C>T

LDLR · NP_000518.1:p.(Gly207=) · NM_000527.5

GRCh37: chr19:11216203 C>T · GRCh38: chr19:11105527 C>T

Gene: LDLR Transcript: NM_000527.5

Final call

Pathogenic

PVS1 very strong PS4 strong PM2 moderate PP4 supporting

Variant details

Gene

LDLR

Transcript

NM_000527.5

Protein

NP_000518.1:p.(Gly207=)

gnomAD AF

2.4789106674962753e-06 (v4.1)

ClinVar

Pathogenic

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Pathogenic: PVS1 very strong reflects demonstrated aberrant splicing and a stable 75-bp in-frame deletion.

2

Pathogenic: PS4 strong reflects 35 unrelated familial hypercholesterolemia index cases, exceeding the VCEP threshold of 10.

3

Pathogenic: PM2 moderate reflects a gnomAD v4.1 group maximum FAF of 6.8e-7, below 0.0002.

4

Pathogenic: PP4 supporting reflects clinically diagnosed familial hypercholesterolemia after known alternative molecular causes were excluded.

Final determination: Under ACMG/AMP 2015 Richards Table 5, one very strong pathogenic criterion plus at least one strong pathogenic criterion supports Pathogenic; the applied PVS1 very strong and PS4 strong satisfy this rule, with PM2 moderate and PP4 supporting also applied.

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	Met	Met, very strong: c.621C>T causes a stable mRNA with a demonstrated 75-bp in-frame deletion, removing 25 LDLR amino acids.	cspec pvs1_variant_assessment PMID:18400033
PS1	N/A	Not applicable: c.621C>T is synonymous, but the VCEP PS1 rule requires a missense variant predicting the same amino-acid change.	cspec pvs1_variant_assessment
PS2	Not assessed	Not assessed: confirmed parental genotypes and documented absence of family history are not available for the patient.	cspec
PS3	Not assessed	Not assessed: aberrant splicing was shown, but the VCEP requires RNA transcript confirmation by sequencing for PS3 Supporting and that confirmation was not documented.	cspec PMID:18400033 PMID:31578082
PS4	Met	Met strong: PMID:18400033 reports 35 unrelated FH index cases, exceeding the VCEP threshold of ≥10, and grpmax FAF 6.8e-7 satisfies PM2.	cspec PMID:18400033 PMID:10735632 gnomad_v4
PM1	N/A	Not applicable: the variant is synonymous at exon 4, while the VCEP PM1 rule requires a missense variant in exon 4 or at a specified conserved cysteine.	cspec pvs1_variant_assessment
PM2	Met	Met at Moderate: gnomAD v4.1 group maximum FAF is 6.8e-7, below the VCEP PM2 PopMax MAF threshold of 0.0002.	cspec gnomad_v4
PM3	Not assessed	Not assessed: two homozygous FH cases were reported, but no single pathogenic partner variant in trans was documented, although group maximum FAF was 6.8e-7.	cspec PMID:18400033 gnomad_v4
PM4	N/A	Not applicable: c.621C>T is a synonymous single-nucleotide substitution, not a VCEP-defined in-frame deletion, insertion, or whole-exon duplication.	cspec pvs1_variant_assessment gnomad_v4 PMID:18400033
PM5	N/A	Not applicable: c.621C>T is synonymous, but both VCEP PM5 routes require a missense variant predicting a different amino-acid change.	cspec pvs1_variant_assessment
PM6	Not assessed	Not assessed: PM6 defers to PS2, but no documented de novo occurrence or parental testing is available.	cspec
PP1	Not assessed	Not assessed: 35 index cases and 62 relatives were reported, but informative-meiosis counts and required LDL-C phenotype data are unavailable.	cspec PMID:18400033
PP2	N/A	Not applicable: the VCEP excludes PP2 for this gene.	cspec
PP3	Not assessed	Not assessed: the VCEP requires MaxEntScan for splice-impact PP3, but only SpliceAI max delta 0.981 and SPLICESITEFINDER evidence are available.	cspec spliceai PMID:18400033
PP4	Met	Met supporting: the variant was identified in clinically diagnosed FH patients after known alternative molecular causes were excluded, and grpmax FAF 6.8e-7 satisfies PM2.	cspec PMID:18400033 gnomad_v4
PP5	N/A	Not applicable: the LDLR FH VCEP excludes PP5 and states that it is not for use.	cspec
BA1	Not met	Not met: gnomAD v4.1 group maximum FAF is 6.8e-7, far below the VCEP BA1 threshold of 0.005.	cspec gnomad_v4
BS1	Not met	Not met: gnomAD v4.1 group maximum FAF is 6.8e-7, below the VCEP BS1 threshold of 0.002.	cspec gnomad_v4
BS2	Not assessed	Not assessed: gnomAD v4.1 reports 0 homozygotes but lacks the required normolipidemic, untreated adult phenotype data and qualifying heterozygote count.	cspec gnomad_v4
BS3	Not assessed	Not assessed: no VCEP-eligible benign whole-cycle or specified RNA/splicing assay showing the required greater-than-90% activity was reported for this variant.	cspec PMID:18400033 PMID:31578082
BS4	Not assessed	Not assessed: no two unrelated families with at least two informative meioses each and an unaffected carrier below the LDL-C 50th centile are documented.	cspec
BP1	N/A	Not applicable: the VCEP excludes BP1 for this gene.	cspec
BP2	Not assessed	Not assessed: FH cohorts included heterozygous patients, but no pathogenic partner variant in LDLR, APOB, or PCSK9 with documented trans phase was reported.	cspec PMID:10735632 PMID:18400033
BP3	N/A	Not applicable: the VCEP excludes BP3 for this gene.	cspec
BP4	Not assessed	Not assessed: the VCEP requires MaxEntScan for no-splice-impact BP4, while available SpliceAI predicts impact with max delta 0.981.	cspec spliceai PMID:18400033
BP5	N/A	Not applicable: the LDLR FH VCEP excludes BP5 for this VCEP.	cspec
BP6	N/A	Not applicable: the LDLR FH VCEP excludes BP6 and states that it is not for use.	cspec
BP7	Not assessed	Not assessed: the variant is synonymous, but BP7 requires BP4 and the VCEP-required MaxEntScan no-impact result is unavailable.	cspec spliceai PMID:18400033

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