Variant classification summary

NM_001360.3:c.964-1G>C

DHCR7 · NP_001351.2:p.? · NM_001360.3

GRCh37: chr11:71146886 C>G · GRCh38: chr11:71435840 C>G

Gene: DHCR7 Transcript: NM_001360.3

Final call

Pathogenic

PVS1 strong PS3 strong PS4 strong PM3 moderate PP3 moderate

Variant details

Gene

DHCR7

Transcript

NM_001360.3

Protein

NP_001351.2:p.?

gnomAD AF

0.007446436160904023 (v4.1)

ClinVar

Pathogenic

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Pathogenic: PVS1 strong reflects canonical splice disruption with a frameshift and inactive truncated DHCR7 protein.

2

Pathogenic: PS3 strong reflects variant-specific RNA and enzyme evidence of aberrant splicing and lost DHCR7 activity.

3

Pathogenic: PS4 strong reflects exact-variant enrichment in SLOS probands, with OR 155.75 and a confidence interval excluding 1.0.

4

Pathogenic: PM3 moderate reflects compound-heterozygous occurrence in affected SLOS patients.

5

Pathogenic: PP3 moderate reflects a SpliceAI max delta of 0.992, indicating a deleterious splice effect.

Final determination: Under the generic ACMG/AMP 2015 fallback, at least two strong pathogenic criteria are sufficient for Pathogenic; this case has PVS1, PS3, and PS4 at strong strength, with additional PM3 and PP3 support.

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 (strong): canonical splice disruption causes a frameshift and inactive protein, but the premature stop lies in terminal exon 9 and is expected to escape NMD, requiring a one-tier downgrade.	pvs1_generic_framework PMID:10710236 PMID:10814720 PMID:11427181
PS1	N/A	Not applicable: PS1 requires a missense variant, and this is a canonical splice-site variant.	generic_acmg_combination_rules
PS2	Not met	Not met: parental testing showed inheritance in five pedigrees, with paternal origin in three and maternal origin in two, rather than a confirmed de novo event.	PMID:10710236
PS3	Met	Met, strong: RT-PCR showed 134-base intron retention and frameshifting, while enzyme assays confirmed inactive DHCR7 in homozygous patients.	PMID:10814720 PMID:11427181
PS4	Met	Met: exact-variant case-control counts yield OR 155.75 (95% CI 19.17-1265.18), exceeding the PS4 threshold >5.0 with a confidence interval excluding 1.0.	PMID:10710236
PM1	N/A	Not applicable: PM1 requires a missense variant, and this is a canonical splice-site variant.	generic_acmg_combination_rules
PM2	Not met	Not met: gnomAD v4.1 allele frequency is 0.744644%, exceeding the PM2 supporting threshold of 0.01% by more than seventyfold.	gnomad_v4 gnomad_v2 PMID:10710236 PMID:25741868
PM3	Met	Met at moderate strength: c.964-1G>C occurred in compound-heterozygous affected SLOS patients, including 8 compound heterozygotes among 13 patients in one study.	PMID:11427181 PMID:10710236
PM4	N/A	Not applicable: PM4 requires a protein-length change, and this is a canonical splice-site variant.	pvs1_generic_framework generic_acmg_combination_rules
PM5	N/A	Not applicable: PM5 requires a missense variant, and this is a canonical splice-site variant.	generic_acmg_combination_rules
PM6	Not met	Not met: parental testing identified paternal transmission in three and maternal transmission in two of five variant-positive pedigrees, so de novo origin is not supported.	PMID:10710236
PP1	Not assessed	Not assessed: five pedigrees show parental transmission to probands, but no multiple affected family members with co-segregation are documented.	PMID:10710236
PP2	N/A	Not applicable: PP2 requires a missense variant, and this is a canonical splice-site variant.	generic_acmg_combination_rules
PP3	Met	Met at moderate strength: SpliceAI max delta 0.992 exceeds the >=0.5 PP3 threshold for this intronic splice-site variant.	spliceai
PP4	Not assessed	Not assessed: the available record lacks the current patient's phenotype or family history needed to establish a highly specific single-gene SLOS presentation.
PP5	Not met	Not met: ClinVar has zero exact-variant expert-panel submissions, and the available literature is independently reviewable rather than unavailable for evaluation.	clinvar PMID:10814720 PMID:10995508 PMID:11427181
BA1	Not met	Not met: gnomAD v4.1 grpmax FAF is 0.906082%, below the 5% BA1 threshold, despite a 1.21619% Ashkenazi Jewish popmax point estimate.	gnomad_v4 gnomad_v2
BS1	Not met	Not met: gnomAD v4.1 grpmax FAF is 0.906082%, below the generic 1% BS1 threshold, and the higher Ashkenazi Jewish popmax is not the required FAF.	gnomad_v4 gnomad_v2
BS2	Not met	Not met: gnomAD v4.1 and v2.1 report zero homozygotes, and the literature reports only a heterozygous control, not a healthy adult homozygote.	gnomad_v4 gnomad_v2 PMID:10710236
BS3	Not assessed	Not assessed: available assays show aberrant splicing and lost DHCR7 activity, with no validated normal-function result for the variant.
BS4	Not assessed	Not assessed: no affected relatives lacking the variant are documented, and the available pedigrees do not establish non-segregation.	PMID:10710236
BP1	N/A	Not applicable: BP1 requires a missense variant, and this is a canonical splice-site variant.	generic_acmg_combination_rules
BP2	Not met	Not met: DHCR7 disease is recessive, and the evidence shows homozygous or compound-heterozygous affected patients rather than a qualifying cis observation or dominant trans configuration.	PMID:11427181 PMID:10710236
BP3	N/A	Not applicable: BP3 requires an in-frame indel in a repeat region, and this is a canonical splice-site variant.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: SpliceAI max delta 0.992 is above the <=0.1 BP4 threshold, indicating predicted splice impact rather than no impact.	spliceai
BP5	Not assessed	Not assessed: no qualifying case is documented with this variant plus an established alternate molecular basis for the disease.
BP6	Not met	Not met: no exact-variant ClinVar expert-panel benign or likely-benign classification is present; available ClinVar assertions are pathogenic laboratory submissions.	clinvar
BP7	N/A	Not applicable: BP7 requires a synonymous variant, and this is a canonical splice-site variant.	generic_acmg_combination_rules

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