Submissions for variant NM_000260.4(MYO7A):c.1142C>T (p.Thr381Met)

gnomAD frequency: 0.00002  dbSNP: rs782681743

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000667999	SCV000792537	uncertain significance	Autosomal recessive nonsyndromic hearing loss 2; Usher syndrome type 1	2017-06-30	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001111948	SCV001269558	uncertain significance	Autosomal recessive nonsyndromic hearing loss 2	2017-04-27	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	RCV001111949	SCV001269559	uncertain significance	Usher syndrome type 1	2017-04-27	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	RCV001112401	SCV001270058	uncertain significance	Autosomal dominant nonsyndromic hearing loss 11	2017-04-27	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.
Invitae	RCV002530732	SCV003440354	likely benign	not provided	2023-12-13	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003323668	SCV004030134	uncertain significance	not specified	2023-07-20	criteria provided, single submitter	clinical testing	Variant summary: MYO7A c.1142C>T (p.Thr381Met) results in a non-conservative amino acid change located in the motor domain (IPR001609) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 194800 control chromosomes (i.e., 11 heterozygotes), predominantly at a frequency of 0.0007 within the East Asian subpopulation in the gnomAD database. Although this frequency is not significantly higher than estimated for a pathogenic variant in MYO7A causing autosomal recessive Usher Syndrome (5.6e-05 vs 0.0061), the lack of complete phenotype data on the individuals within this cohort and this frequency does not allow conclusions about variant significance for either dominant or recessive association with disease. c.1142C>T has been reported in the literature predominantly in East Asian cohorts among several unrelated heterozygous individuals with hearing loss (e.g.,Li_2021), including as a de novo variant (e.g., Su_2009), and has also been identified in heterozygous affected individuals from the same family, suggesting the variant may segregate with disease (e.g., Wu_2013). Additionally, the variant has been reported in at least two compound heterozygous individuals with hearing loss, once in trans with a variant of uncertain significance (e.g., Yan_2016) and also in trans with a variant associated with autosomal dominant disease and recognized as likely pathogenic (e.g., Pan_2022). These reports therefore do not provide unequivocal conclusions about association of the variant with Usher Syndrome or hearing loss. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33724713, 35640668, 19299023, 23451214, 27344577). Three submitters have reported clinical-significance assessments for this variant to ClinVar after 2014; two submitters classified the variant as VUS, and one submitter classified it as likely benign. Based on the evidence outlined above, a lack of experimental evidence on the variant effect, and ambiguity related to the exact inheritance pattern (dominant or recessive), the variant was classified as uncertain significance.