Submissions for variant NM_000260.4(MYO7A):c.5899C>T (p.Arg1967Ter)

gnomAD frequency: 0.00002  dbSNP: rs376764423

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000844723	SCV000204929	pathogenic	Rare genetic deafness	2014-07-14	criteria provided, single submitter	clinical testing	The Arg1967X variant in MYO7A has been previously reported in one individual wit h Usher syndrome who was homozygous, and three affected family members were also found to be homozygous for the variant (Shahzad 2013). This variant has also be en identified in 1/8354 European American chromosomes by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu; dbSNP rs376764423). Although this var iant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This nonsense variant leads to a premature termination codon at position 1967, which is predicted to lead to a tr uncated or absent protein. In summary, this variant meets our criteria to be cla ssified as pathogenic (http://pcpgm.partners.org/LMM).
Illumina Laboratory Services, Illumina	RCV004528890	SCV000374493	likely pathogenic	MYO7A-related disorder	2016-06-14	criteria provided, single submitter	clinical testing	The c.5899C>T (p.Arg1967Ter) stop-gained variant has been reported in three studies in patients with Usher syndrome and is found in four affected siblings from a consanguineous family in a homozygous state, in one patient in a compound heterozygous state, and in one patient in a heterozygous state who also carried a second missense variant, but the phase is unknown (Shahzad et al. 2013; Bujakowska et al. 2014; Ellingford et al. 2016). The variant is also found in one unaffected parent in a heterozygous state (Bujakowska et al. 2014). One affected relative from the extended consanguineous family did not carry the p.Arg1967Ter variant. The variant was absent from 190 controls (Shahzad et al. 2013) but is reported at a frequency of 0.00005 in the European (Non-Finnish) population of the Exome Aggregation Consortium. Based on the evidence in the literature and the potential impact of stop-gained variants, the p.Arg1967Ter variant is classified as likely pathogenic for MYO7A-related disorders.
GeneDx	RCV001544789	SCV001763988	pathogenic	not provided	2020-10-15	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 27941802, 26872967, 27208204, 25468891, 23770805, 27460420, 29048421)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001544789	SCV002230899	pathogenic	not provided	2023-12-27	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg1967*) in the MYO7A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MYO7A are known to be pathogenic (PMID: 8900236, 25404053). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with clinical features of Usher syndrome (PMID: 23770805). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 178495). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000411148	SCV005051868	pathogenic	Autosomal recessive nonsyndromic hearing loss 2	2024-02-01	criteria provided, single submitter	curation
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000155243	SCV005398017	pathogenic	Usher syndrome type 1	2024-09-22	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with deafness autosomal dominant 11 (MIM#601317), deafness autosomal recessive 2 (MIM#600060) and Usher syndrome, type 1B (MIM#276900). In addition, dominant negative is the suggested mechanism for missense variants in autosomal dominant inheritance (OMIM, PMID: 23383098). (I) 0108 - This gene is associated with both recessive and dominant disease. While the genotype-phenotype correlation is unestablished, missense variants causing autosomal dominant inheritance are rare and are not localised to a specific protein region (OMIM). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2, v3) <0.01 (3 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported several times as pathogenic and likely pathogenic, and observed in homozygous and compound heterozygous individuals, with one referrer specifying the individual was affected with Usher syndrome (ClinVar). (SP) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant (NM_000260.3(MYO7A):c.496del; p.(Glu166Argfs*5)) in a recessive disease. (I) 1205 - This variant has been shown to be maternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Fulgent Genetics, Fulgent Genetics	RCV005008062	SCV005629485	pathogenic	Autosomal dominant nonsyndromic hearing loss 11; Autosomal recessive nonsyndromic hearing loss 2; Usher syndrome type 1	2024-03-19	criteria provided, single submitter	clinical testing
Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals	RCV000225571	SCV000282593	likely pathogenic	Retinal dystrophy		no assertion criteria provided	clinical testing
Counsyl	RCV000155243	SCV000487452	likely pathogenic	Usher syndrome type 1	2016-11-10	no assertion criteria provided	clinical testing
Counsyl	RCV000411148	SCV000487453	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 2	2016-11-10	no assertion criteria provided	clinical testing
Natera, Inc.	RCV001831964	SCV002088527	pathogenic	Usher syndrome type 1B	2021-01-20	no assertion criteria provided	clinical testing