Submissions for variant NM_000260.4(MYO7A):c.5573T>C (p.Leu1858Pro)

gnomAD frequency: 0.00001  dbSNP: rs368657015

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036193	SCV000059845	pathogenic	Rare genetic deafness	2016-08-23	criteria provided, single submitter	clinical testing	The p.Leu1858Pro variant in MYO7A has been reported in at least 10 probands with Usher syndrome who were either homozygous for the variant or compound heterozyg ous with a second pathogenic or likely pathogenic variant in MYO7A (Bharadwaj 20 00, Roux 2006, Jacobson 2008, Blanchet 2007, Roux 2011, LeQuesne Stabej 2012, LM M data). It has been identified in 3/55658 European chromosomes by the Exome Agg regation Consortium (http://exac.broadinstitute.org/; dbSNP rs368657015), which is low enough to be consistent with the carrier frequency in the general populat ion. In summary, this variant meets criteria to be classified as pathogenic for Usher syndrome in an autosomal recessive manner based on its presence in homozyg osity or compound heterozygosity with a second pathogenic allele in many individ uals with Usher syndrome, and low frequency in the general population.
Fulgent Genetics, Fulgent Genetics	RCV000763283	SCV000893927	likely pathogenic	Autosomal dominant nonsyndromic hearing loss 11; Autosomal recessive nonsyndromic hearing loss 2; Usher syndrome type 1	2018-10-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000779082	SCV000915558	pathogenic	MYO7A-Related Disorders	2017-09-14	criteria provided, single submitter	clinical testing	Variants in the MYO7A gene are known to cause MYO7A-related disorders, which include Usher syndrome and autosomal recessive and autosomal dominant forms of nonsyndromic hearing loss. The c.5573T>C (p.Leu1858Pro) variant has been identified in a compound heterozygous state in at least six affected individuals, including five with Usher syndrome type 1 and one with autosomal recessive nonsyndromic hearing loss (Roux et al. 2006; Jacobson et al. 2008; Roux et al. 2011; Le Quesne Stabej et al. 2012; Bademci et al. 2016). One additional individual with Usher syndrome type 1 was heterozygous for the p.Leu1858Pro variant and another missense variant, but the phase of the variants was unclear (Bharadwaj et al. 2000). The variant has not been reported in conjunction with autosomal dominant nonsyndromic hearing loss. The p.Leu1858Pro variant was absent from 2148 control chromosomes and is reported at a frequency of 0.000056 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the collective evidence, the p.Leu1858Pro variant is classified as pathogenic for MYO7A-related disorders. Note: While the p.Leu1858Pro variant has not been reported in conjunction with autosomal dominant nonsyndromic hearing loss, disease risk cannot be ruled out. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV001268401	SCV001447303	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Invitae	RCV001268401	SCV001589412	pathogenic	not provided	2024-01-11	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 1858 of the MYO7A protein (p.Leu1858Pro). This variant is present in population databases (rs368657015, gnomAD 0.006%). This missense change has been observed in individual(s) with Usher syndrome (PMID: 10930322, 16679490, 22135276, 28944237). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 43288). 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%. For these reasons, this variant has been classified as Pathogenic.
The Shared Resource Centre "Genome", Research Centre for Medical Genetics	RCV000668342	SCV002756435	pathogenic	Autosomal recessive nonsyndromic hearing loss 2	2022-11-10	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003407403	SCV004107403	pathogenic	MYO7A-related condition	2023-04-07	criteria provided, single submitter	clinical testing	The MYO7A c.5573T>C variant is predicted to result in the amino acid substitution p.Leu1858Pro. This variant has been reported in the homozygous state or heterozygous state with a second MYO7A variant in multiple individuals with typical or atypical Usher syndrome (Bharadwaj. 2000. PubMed ID: 10930322; Roux et al. 2006. PubMed ID: 16679490; Jacobson et al. 2008. PubMed ID: 18463160; Roux et al. 2011. PubMed ID: 21436283; Le Quesne Stabej et al. 2012. PubMed ID: 22135276; Bademci. 2016. PubMed ID: 26226137; Neuhaus. 2017. PubMed ID: 28944237; Khateb et al. 2019. PubMed ID: 31479088; Bahena et al. 2021. PubMed ID: 34148116). In an least one of the reported individuals, the variant was confirmed to be in trans with a second causative variant (Bademci. 2016. PubMed ID: 26226137). This variant is reported in 0.0055% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-76916599-T-C). It is interpreted as pathogenic or likely pathogenic by multiple submitters to ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/43288). Taken together, this variant is interpreted as pathogenic.
Counsyl	RCV000668342	SCV000792923	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 2	2017-07-24	no assertion criteria provided	clinical testing
Natera, Inc.	RCV001273514	SCV001456625	pathogenic	Usher syndrome type 1B	2020-09-16	no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV001268401	SCV001925511	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001268401	SCV001954676	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001268401	SCV001972645	likely pathogenic	not provided		no assertion criteria provided	clinical testing