ClinVar Miner

Submissions for variant NM_000260.4(MYO7A):c.3719G>A (p.Arg1240Gln) (rs111033178)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000504703 SCV000059774 pathogenic Usher syndrome 2019-07-31 criteria provided, single submitter clinical testing The Arg1240Gln variant in MYO7A has been reported in at least 14 probands with Usher syndrome (Jacobson 2008, Bharadwaj 2000, Gerber 2006, Jaijo 2007, Jaijo 2009, Janecke 1999, Pennings 2006, Pennings 2004, Roux 2006). Eleven of these probands were homozygous or compound heterozygous. It has also segregated in at least one affected sibling as observed by testing in our laboratory, and it has been reported in ClinVar (Variation ID 43218). This variant has been identified in 0.01% (12/80298) of European chromosomes by gnomAD (, which is low enough to be consistent with a recessive allele frequency. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Usher syndrome. ACMG/AMP Criteria applied: PM3_VeryStrong, PM2_Supporting, PP3, PP1_Supporting, PP4.
GeneDx RCV000256123 SCV000321919 pathogenic not provided 2018-05-17 criteria provided, single submitter clinical testing The R1240Q variant in the MYO7A gene has been reported previously in association with Usher syndrome (Bharadwaj et al., 2000; Pennings et al., 2004; Roux et al., 2006; Jacobson et al., 2008). The variant was not observed at any significant frequency in approximately 6300 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. R1240Q is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, this variant is pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000256123 SCV000608608 pathogenic not provided 2019-09-01 criteria provided, single submitter clinical testing
Ambry Genetics RCV000623302 SCV000741118 pathogenic Inborn genetic diseases 2014-09-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected
Fulgent Genetics,Fulgent Genetics RCV000763279 SCV000893923 pathogenic Deafness, autosomal dominant 11; Deafness, autosomal recessive 2; Usher syndrome type 1 2018-10-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000778342 SCV000914542 pathogenic MYO7A-Related Disorders 2018-10-05 criteria provided, single submitter clinical testing The MYO7A c.3719G>A (p.Arg1240Gln) missense variant has been reported in at least 11 studies in which it is found in 26 individuals with Usher syndrome type 1 including five homozygotes, 18 compound heterozygotes, two heterozygotes, and in one individual in a double heterozygous state with a variant in the USH2A gene (Janecke et al. 1999; Bharadwaj et al. 2000; Pennings et al. 2004; Gerber et al. 2006; Pennings et al. 2006; Roux et al. 2006; Jaijo et al. 2007; Jacobsen et al. 2008; Jaijo et al. 2010; Bonnet et al. 2011; Le Quesne Stabej et al. 2012). While this variant has not been reported in conjunction with nonsyndromic hearing loss, disease risk cannot be ruled out. The variant was not found in at least 1075 healthy controls (Janecke et al. 1999; Roux et al. 2006; Jaijo et al. 2010; Bonnet et al. 2011) and is reported at a frequency of 0.000723 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the combined evidence, the p.Arg1240Gln variant is classified as pathogenic for Usher syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000256123 SCV000955876 pathogenic not provided 2020-01-02 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 1240 of the MYO7A protein (p.Arg1240Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs111033178, ExAC 0.2%). This variant has been observed to be homozygous or in combination with another MYO7A variant in individuals affected with Usher syndrome or with clinical features of this condition (PMID: 22135276, 20513143, 21569298, 17361009, 10930322, 21873662, 18463160, 15043528, 16652077) or with non-syndromic deafness (PMID: 27068579, 26969326). In one of these individuals, the variant has been observed on the opposite chromosome (in trans) from a pathogenic variant. This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 43218). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant disrupts the p.Arg1240 amino acid residue in MYO7A. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 24199935), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics RCV001075882 SCV001241523 pathogenic Retinal dystrophy 2019-08-15 criteria provided, single submitter clinical testing
GeneReviews RCV000036122 SCV000268744 pathogenic Usher syndrome type 1 2016-05-19 no assertion criteria provided literature only
NIHR Bioresource Rare Diseases, University of Cambridge RCV000504703 SCV000599121 likely pathogenic Usher syndrome 2015-01-01 no assertion criteria provided research
Counsyl RCV000984006 SCV000788911 pathogenic Deafness, autosomal recessive 2 2017-01-03 no assertion criteria provided clinical testing

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