Submissions for variant NM_000260.4(MYO7A):c.3659C>T (p.Pro1220Leu)

gnomAD frequency: 0.00003  dbSNP: rs727504710

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000155994	SCV000205706	uncertain significance	not specified	2016-06-23	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The p.Pro1220Leu va riant in MYO7A has been reported in 1 Caucasian individual with Usher syndrome w ho also had 2 variants in the USH2A gene sufficient to explain disease and in 1 individual by our laboratory who was also heterozygous for 2 pathogenic variants in 2 different genes (Bonnet 2011, LMM unpublished data). This variant has been identified in 1/9144 European chromosomes by the Exome Aggregation Consortium ( ExAC, http://exac.broadinstitute.org; dbSNP rs727504710). Computational predicti on tools and conservation analyses suggest that this variant may impact the prot ein, though this information is not predictive enough to determine pathogenicity . In summary, while the clinical significance of the p.Pro1220Leu variant is unc ertain, its presence in previously reported affected individuals who had alterna te explanations for the hearing loss suggests a more likely benign role for this variant.
Mendelics	RCV000988611	SCV001138390	uncertain significance	Autosomal recessive nonsyndromic hearing loss 2	2019-05-28	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001054597	SCV001218940	uncertain significance	not provided	2022-10-04	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1220 of the MYO7A protein (p.Pro1220Leu). This variant is present in population databases (rs727504710, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of Usher syndrome (PMID: 21569298). ClinVar contains an entry for this variant (Variation ID: 179208). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Illumina Laboratory Services, Illumina	RCV001113006	SCV001270731	uncertain significance	Usher syndrome type 1	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV000988611	SCV001270732	uncertain significance	Autosomal recessive nonsyndromic hearing loss 2	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001113007	SCV001270733	uncertain significance	Autosomal dominant nonsyndromic hearing loss 11	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Genome-Nilou Lab	RCV001113007	SCV001805893	uncertain significance	Autosomal dominant nonsyndromic hearing loss 11	2021-07-14	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000988611	SCV001805894	uncertain significance	Autosomal recessive nonsyndromic hearing loss 2	2021-07-14	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001113006	SCV001805895	uncertain significance	Usher syndrome type 1	2021-07-14	criteria provided, single submitter	clinical testing
GeneDx	RCV001054597	SCV002038783	uncertain significance	not provided	2023-04-10	criteria provided, single submitter	clinical testing	Observed in a patient with Usher syndrome in published literature (Bonnet C et al., 2011); of note, this patient was compound heterozygous for USH2A variants; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30245029, 21569298, 32279305, 34426522)
Fulgent Genetics, Fulgent Genetics	RCV002505174	SCV002816832	uncertain significance	Autosomal dominant nonsyndromic hearing loss 11; Autosomal recessive nonsyndromic hearing loss 2; Usher syndrome type 1	2022-05-31	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001272513	SCV001454585	uncertain significance	Usher syndrome type 1B	2020-09-16	no assertion criteria provided	clinical testing