ClinVar Miner

Submissions for variant NM_000260.4(MYO7A):c.5510T>C (p.Leu1837Pro)

gnomAD frequency: 0.00001  dbSNP: rs1385324903
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Baylor Genetics RCV001334338 SCV001527151 uncertain significance Autosomal dominant nonsyndromic hearing loss 11 2018-08-22 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Invitae RCV001855514 SCV002240320 pathogenic not provided 2023-11-17 criteria provided, single submitter clinical testing This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 1837 of the MYO7A protein (p.Leu1837Pro). This variant is present in population databases (no rsID available, gnomAD 0.007%). This missense change has been observed in individuals with autosomal recessive MYO7A-related conditions (PMID: 26338283, 27610647, 29625443). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 553592). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MYO7A protein function with a positive predictive value of 95%. This variant disrupts the p.Leu1837 amino acid residue in MYO7A. Other variant(s) that disrupt this residue have been observed in individuals with MYO7A-related conditions (PMID: 27460420), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV003152610 SCV003841230 likely pathogenic Autosomal recessive nonsyndromic hearing loss 2 criteria provided, single submitter clinical testing
King Laboratory, University of Washington RCV003155267 SCV003844138 likely pathogenic Usher syndrome type 1 2023-02-28 criteria provided, single submitter research This variant occurred in compound heterozygosity with a likely pathogenic MYO7A missense variant in a patient with Usher syndrome including bilateral sensorineural hearing loss of onset <18 years, in a study of pediatric hearing loss conducted by the King Laboratory (Carlson RJ et al. JAMA-OtoHNS 2023). This patient's family has no other history of hearing loss. This variant is a missense at a highly conserved site in a MyTH4 domain of the MYO7A protein and is predicted to be damaging by multiple in-silico tools. As of January 2023, this variant has been reported to ClinVar with conflicting interpretations and is found in 2 heterozygotes on gnomAD. Based on consistently predicted functional effect, compound heterozygosity with a known likely pathogenic variant, and goodness of fit of genotype to phenotype, we conclude that this variant is likely pathogenic.
Counsyl RCV000669072 SCV000793773 uncertain significance Autosomal recessive nonsyndromic hearing loss 2; Usher syndrome type 1 2017-08-30 flagged submission clinical testing

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