Usher syndrome: genes and variants

Genes linked to Usher syndrome

• MYO7A: Unconventional myosin-VIIa

  Its actin-based motor supports stereocilia organization in inner-ear hair cells and transport processes in retinal cells. Biallelic pathogenic variants cause Usher syndrome type 1B, while other alleles can cause nonsyndromic hearing loss.

  80 disease-causing and 179 uncertain variants in MYO7A are linked to Usher syndrome.

• USH2A: Usherin

  It helps organize extracellular and membrane structures required for cochlear hair-cell and photoreceptor function. Biallelic pathogenic variants cause Usher syndrome type 2A or nonsyndromic retinitis pigmentosa and can also produce isolated hearing loss.

  40 disease-causing and 223 uncertain variants in USH2A are linked to Usher syndrome.

• PCDH15: Protocadherin-15

  It forms part of the tip-link complex that converts mechanical deflection of inner-ear hair bundles into electrical signals and also supports photoreceptor structure. Biallelic pathogenic variants cause Usher syndrome type 1F or nonsyndromic hearing loss.

  4 disease-causing and 198 uncertain variants in PCDH15 are linked to Usher syndrome.

• USH1C: Harmonin

  It organizes protein complexes in inner-ear hair-cell stereocilia and photoreceptor structures. Biallelic pathogenic variants cause Usher syndrome type 1C with congenital severe hearing loss and progressive retinitis pigmentosa, or in some alleles isolated deafness.

  4 disease-causing and 53 uncertain variants in USH1C are linked to Usher syndrome.

Weakly linked (only a few uncertain records): ATP6V1B1, BBS1, CRX, PRPH2 and VSIR.

Where Usher syndrome variants cluster

• MYO7A Myosin motor (positions 65–741): 37 of 80 disease-causing changes, 1.5× more than its size predicts.
• USH2A Laminin EGF-like 1 (positions 518–574): 3 of 40 disease-causing changes, 6.8× more than its size predicts.
• USH2A Laminin G-like 2 (positions 1714–1891): 4 of 40 disease-causing changes, 2.9× more than its size predicts.
• USH2A Laminin N-terminal (positions 271–517): 4 of 40 disease-causing changes, 2.1× more than its size predicts.

Known disease-causing variants in Usher syndrome

Showing 60 of 128.

Uncertain variants in Usher syndrome that look disease-causing

Which prediction tools work for Usher syndrome

How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).

• MetaLR: 96 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• REVEL: 94 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• PolyPhen-2: 91 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CATVariant: 90 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CADD: 90 out of 100
• SIFT: 89 out of 100
• phyloP: 77 out of 100

Same protein, different disease

• Autosomal recessive nonsyndromic hearing loss 4 is also caused by MYO7A variants; they fall partly in the same places as the Usher syndrome variants (26 disease-causing).
• Rare genetic deafness is also caused by MYO7A variants; they fall mostly in different places as the Usher syndrome variants (23 disease-causing).
• Autosomal dominant nonsyndromic hearing loss is also caused by MYO7A variants; they fall partly in the same places as the Usher syndrome variants (13 disease-causing).
• Hearing loss is also caused by MYO7A variants; they fall mostly in different places as the Usher syndrome variants (4 disease-causing).
• Nonsyndromic genetic hearing loss is also caused by MYO7A variants; they fall in the same places as the Usher syndrome variants (4 disease-causing).
• Retinitis pigmentosa is also caused by USH2A variants; they fall mostly in different places as the Usher syndrome variants (23 disease-causing).
• Autosomal recessive nonsyndromic hearing loss 4 is also caused by PCDH15 variants; they fall mostly in different places as the Usher syndrome variants (6 disease-causing).

Diseases related to Usher syndrome

• Autosomal recessive nonsyndromic hearing loss 4, also linked to MYO7A, PCDH15 and USH1C
• Rare genetic deafness, also linked to MYO7A, PCDH15 and USH2A
• Hearing loss, also linked to MYO7A, PCDH15 and USH1C
• Deafness, also linked to MYO7A, PCDH15 and USH1C
• Retinitis pigmentosa, also linked to MYO7A and USH2A
• Autosomal dominant nonsyndromic hearing loss, also linked to MYO7A
• Cone-rod dystrophy, also linked to USH2A
• Nonsyndromic genetic hearing loss, also linked to MYO7A
• Monogenic hearing loss, also linked to MYO7A
• Retinal disorder, also linked to USH2A
• Auditory neuropathy, also linked to MYO7A
• Autosomal recessive retinitis pigmentosa, also linked to USH2A

Frequently asked questions

Which genes are linked to Usher syndrome?

In CATVariant, Usher syndrome is linked to 4 analyzed proteins: MYO7A (Unconventional myosin-VIIa), USH2A (Usherin), PCDH15 (Protocadherin-15) and USH1C (Harmonin).

How many genetic variants are linked to Usher syndrome?

1,000 variants: 128 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 656 are of uncertain significance or have conflicting reports.

Which uncertain variants in Usher syndrome look disease-causing?

3 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example MYO7A R1168W, MYO7A A2009D and MYO7A R666Q. These are leads for expert review, not diagnoses.

Which variant effect predictor works best for Usher syndrome?

Among tools not trained on clinical labels, CADD separates this disease's known disease-causing variants from harmless ones best (AUROC 0.90, based on 100 disease-causing and 120 harmless variants).

About this data

Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.

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