Variant: NM_000260.4(MYO7A):c.6560G>A (p.Gly2187Asp)

CA278713

43335 (ClinVar)

Gene: MYO7A

Condition: Usher syndrome

Inheritance Mode: Autosomal recessive inheritance

UUID: 8815458c-46db-44af-b7e7-82344035be79

Approved on: 2019-11-26

Published on: 2019-11-26

HGVS expressions

NM_000260.4:c.6560G>A
NM_000260.4(MYO7A):c.6560G>A (p.Gly2187Asp)
NC_000011.10:g.77214608G>A
CM000673.2:g.77214608G>A
NC_000011.9:g.76925653G>A
CM000673.1:g.76925653G>A
NC_000011.8:g.76603301G>A
NG_009086.1:g.91344G>A
NG_009086.2:g.91363G>A
ENST00000409709.9:c.6560G>A
ENST00000670577.1:c.4361G>A
ENST00000409619.6:c.6413G>A
ENST00000409709.7:c.6560G>A
ENST00000458169.2:c.3986G>A
ENST00000458637.6:c.6440G>A
ENST00000481328.7:n.5110G>A
ENST00000605744.1:n.2074G>A
NM_000260.3:c.6560G>A
NM_001127180.1:c.6440G>A
NM_001127180.2:c.6440G>A
NM_001369365.1:c.6413G>A

Likely Pathogenic

• Met criteria codes: PP3 PP4 PM2 PM3

• Not Met criteria codes: PS1 PS2 PS3 PS4 PP1 PP2 PM6 PM1 PM5 PM4 PVS1 BA1 BS2 BS1 BS4 BS3 BP5 BP7 BP4 BP3 BP1 BP2

Expert Panel

Hearing Loss VCEP

Criteria Specification Information

Evidence submitted by expert panel

Hearing Loss VCEP

The allele frequency of the p.Gly2187Asp variant in the MYO7A gene is 0.001% (1//84018) of non-Finnish European chromosomes by gnomAD, which is a low enough frequency to apply PM2 based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss (PM2). This variant has been observed presumed in trans with a pathogenic variant in one individual with Usher syndrome type 1, and confirmed in trans with a different pathogenic variant in another in patient with hearing loss and vestibular dysfunction (PM3; PMID: 10930322; Partners LMM internal data RCV000036241.3). One of these patients with the variant in this gene also displayed features consistent with Usher syndrome, a condition highly specific for MYO7A (PP4; PMID: 10930322). The REVEL computational prediction analysis tool produced a score of 0.915, which is above the threshold necessary to apply PP3. Functional evidence suggests this variant may disrupt necessary protein-protein interactions between MYO7A and USH1C; however PS3 will not be applied as this assay did not meet criteria specified by the ClinGen Hearing Loss Expert Panel (PMID: 28439001). In summary, this variant meets criteria to be classified as likely pathogenic for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel (PM2, PM3, PP4, PP3).

Met criteria codes

• PP3: REVEL is 0.915
• PP4: All patients in Bharadwaj et al had profound congenital deafness and RP
• PM2: 0.001% in European non-Finnish (1/84018 chromosomes)
• PM3: In addition to the observation in Bharadwaj, LMM has observed this variant in an effected patient and presumed in trans with a pathogenic or likely pathogenic MYO7A variant. 1 point total for PM3_Moderate

Not Met criteria codes

• PS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS3: Disrupts interaction with the PDZ3 domain of USH1C. However, the experiment does not have great controls and this type of assay is not listed as adequate for PS3_Supporting
• PS4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM6: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM5: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PVS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BA1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP5: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP7: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline