SMCHD1

Chr 18ADDigenic dominant

structural maintenance of chromosomes flexible hinge domain containing 1

Also known as: BAMS, FSHD2

NCBI Gene: 23347 ENSG00000101596 UniProt: A6NHR9 OMIM: 614982

The protein is a non-canonical structural maintenance of chromosomes (SMC) family member that regulates chromatin architecture through epigenetic silencing, promotes heterochromatin formation and X chromosome inactivation, and participates in DNA double-strand break repair. Mutations cause Bosma arhinia microphthalmia syndrome and facioscapulohumeral muscular dystrophy 2 (digenic form), following autosomal dominant or digenic dominant inheritance patterns. The gene is highly constrained against loss-of-function variants, reflecting its essential cellular functions.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

MultiplemechanismAD/Digenic dominantLOEUF 0.152 OMIM phenotypes

Clinical Summary— SMCHD1

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Gene-Disease Validity (ClinGen)

arhinia, choanal atresia, and microphthalmia · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

42 unique Pathogenic / Likely Pathogenic· 280 VUS of 498 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — SMCHD1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint

0.15LOEUF

pLI 1.000

Z-score 8.56

OE 0.09 (0.05–0.15)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint

3.63Z-score

OE missense 0.67 (0.63–0.71)

634 obs / 948.8 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios

LoF OE0.09 (0.05–0.15)

0≤0.351.4

Missense OE0.67 (0.63–0.71)

0≤0.61.4

Synonymous OE0.94

0≤1.21.6

LoF obs/exp: 9 / 102.5Missense obs/exp: 634 / 948.8Syn Z: 0.80

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveSMCHD1-related isolated arhinia/Bosma arhinia syndromeOTHERAD

0.2997th %ile

GOF

0.2895th %ile

LOF

0.66top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · 1 literature citation · 62% of P/LP variants are LoF · LOEUF 0.15

GOF1 literature citation

Literature Evidence

GOFBiochemical tests and in vivo assays in Xenopus laevis embryos suggest that these mutations may behave as gain-of-function alleles. This finding is in contrast to the loss-of-function mutations in SMCHD1 that have been associated with facioscapulohumeral muscular dystrophy (FSHD) type 2PMID:28067911

LOFTogether, these results support haploinsufficiency of SMCHD1 as a cause of D4Z4 hypomethylation in unrelated FSHD2 kindreds.PMID:23143600

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.