Variant: NM_000260.3(MYO7A):c.1849T>C (p.Ser617Pro)

CA6197628

438172 (ClinVar)

Gene: MYO7A

Condition: Usher syndrome

Inheritance Mode: Autosomal recessive inheritance

UUID: 91d8a5fd-ca4f-426d-9b06-68e7858e7d7e

HGVS expressions

NM_000260.3:c.1849T>C
NM_000260.3(MYO7A):c.1849T>C (p.Ser617Pro)
NC_000011.10:g.77172799T>C
CM000673.2:g.77172799T>C
NC_000011.9:g.76883845T>C
CM000673.1:g.76883845T>C
NC_000011.8:g.76561493T>C
NG_009086.1:g.49536T>C
NM_001127179.2:c.1849T>C
NM_001127180.1:c.1849T>C
NM_000260.4:c.1849T>C
ENST00000409619.6:c.1816T>C
ENST00000409709.7:c.1849T>C
ENST00000409893.5:c.1849T>C
ENST00000458637.6:c.1849T>C
ENST00000620575.4:c.1849T>C

Uncertain Significance

• Met criteria codes: PM3_Supporting PP3 PP4 PM2_Supporting

• Not Met criteria codes: BP4 PP1 BA1 BS1

Expert Panel

Hearing Loss VCEP

Criteria Specification Information

Evidence submitted by expert panel

Hearing Loss VCEP

The p.Ser617Pro variant was present in 0.008716% (2/22946) of South Asian chromosomes in gnomAD, which is a low enough frequency to apply PM2_Supporting based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss (PM2_Supporting; gnomad.broadinstitute.org). This variant has been reported in 1 South Asian proband with Usher syndrome (PP4; PMID: 28041643). This individual was compound heterozygous with a pathogenic variant (VCV000438178.1) which was assumed to be in trans (PM3_Supporting). Of note, this variant was observed in 2 additional probands; however, it was not specified whether or not these individuals presented with phenotypes other than hearing loss (PMID: 27344577, 30303587). Computational prediction tools and conservation analysis suggest that the p.Ser617Pro variant may impact the protein (PP3). In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting, PM3_Supporting, PP3, PP4.

Met criteria codes

• PM3_Supporting: Observed in 1 individual with Usher syndrome who also carried the Asp1613ValfsTer32 variant (VCV000438178.1), assumed to be in trans (Carss et al. 2017; 0.5 pts). Points were not assigned to probands from Richard et al. or Yan et al. because no phenotypes besides HL were investigated/probands were not diagnosed with Usher syndrome.
• PP3: REVEL score 0.922. Splicing is not predicted to be impacted. No animals in UCSC database have a mutation at this codon.
• PP4: Identified in 1 individual confirmed by molecular diagnosis and phenotyping to have Usher syndrome.
• PM2_Supporting: Present in 0.008716% (2/22946) of South Asian alleles in gnomAD.

Not Met criteria codes

• BP4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP1: This variant segregated with hearing loss 3 times in 1 family, but it was not clear if the children had Usher syndrome or NSHL
• BA1: 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

Approved on: 2019-08-26

Published on: 2019-10-07