ClinVar Miner

Submissions for variant NM_000260.4(MYO7A):c.4450C>T (p.Leu1484Phe)

gnomAD frequency: 0.00006  dbSNP: rs200416912
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000036145 SCV000059797 uncertain significance not specified 2013-03-11 criteria provided, single submitter clinical testing The Leu1484Phe variant in MYO7A has been reported in one individual with the cli nical features of Usher syndome type I who carried a second missense variant in MYO7A (Jaijo 2006), but has not been identified in any additional affected indiv iduals. However, this variant has been seen in 0.04% (3/8342) of European Americ an chromosomes in a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs200316912); though this frequency is not h igh enough to rule out a pathogenic rule. Computational analyses (biochemical am ino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provid e strong support for or against an impact to the protein. In summary, additional information is needed to determine the clinical significance of this variant.
Illumina Laboratory Services, Illumina RCV000778344 SCV000914544 uncertain significance Usher syndrome type 1 2017-11-21 criteria provided, single submitter clinical testing The MYO7A gene is one of at least nine genes in which variants are known to cause Usher syndrome and this gene is associated with Usher syndrome type 1 (USH1) and Usher syndrome type 2 (USH2). The c.4450C>T (p.Leu1484Phe) variant has been reported in a compound heterozygous state with a second missense variant in a Spanish individual with USH1 (Jaijo et al. 2006). The p.Leu1484Phe variant was shown to be absent from 100 control chromosomes and is reported at a frequency of 0.000360 in the European American population of the Exome Sequencing Project. It is predicted to affect the structure of the protein as it occurs in the folding core of the FERM domain (Wu et al. 2011); however, functional studies of its effects have not been conducted. The evidence for this variant is limited. The p.Leu1484Phe variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for Usher syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Illumina Laboratory Services, Illumina RCV001113191 SCV001270947 uncertain significance Autosomal dominant nonsyndromic hearing loss 11 2018-10-26 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 RCV001113192 SCV001270948 uncertain significance Autosomal recessive nonsyndromic hearing loss 2 2018-10-26 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 RCV001239874 SCV001412776 uncertain significance not provided 2022-10-02 criteria provided, single submitter clinical testing This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 1484 of the MYO7A protein (p.Leu1484Phe). This variant is present in population databases (rs200416912, gnomAD 0.009%). This missense change has been observed in individual(s) with Usher syndrome (PMID: 16470552). ClinVar contains an entry for this variant (Variation ID: 43241). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on 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.
Institute of Human Genetics, University of Leipzig Medical Center RCV000778344 SCV001440960 likely pathogenic Usher syndrome type 1 2024-01-05 criteria provided, single submitter clinical testing This variant was identified as compound-heterozygous with NM_000260.3:c.3283G>A, p.(Glu1095Lys). The variant has often been identified in individuals with autosomal recessive Usher Syndrome (PMID: 16470552, 30245029, 31964843, 33576163, 36672771). In silico predictions suggest a pathogenic effect. The variant has not been observed as homozygous in the general population (gnomAD). It is therefore classified as likely pathogenic with the following ACMG criteria applied: PM3_STR, PM2_SUP, PP3
GeneDx RCV001239874 SCV001985466 uncertain significance not provided 2022-02-28 criteria provided, single submitter clinical testing 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, 34426522, 16470552, 33671976, 33576163)
Myriad Genetics, Inc. RCV000778344 SCV002060323 uncertain significance Usher syndrome type 1 2021-10-01 criteria provided, single submitter clinical testing NM_000260.3(MYO7A):c.4450C>T(L1484F) is a missense variant classified as a variant of uncertain significance in the context of MYO7A-related disorders. L1484F has been observed in cases with relevant disease (PMID: 16470552). Functional assessments of this variant are not available in the literature. L1484F has been observed in population frequency databases (gnomAD: NFE 0.01%). In summary, there is insufficient evidence to classify NM_000260.3(MYO7A):c.4450C>T(L1484F) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening.
Natera, Inc. RCV001273499 SCV001456610 uncertain significance Usher syndrome type 1B 2020-09-16 no assertion criteria provided clinical testing

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