Submissions for variant NM_000260.4(MYO7A):c.2187+1G>A

gnomAD frequency: 0.00001  dbSNP: rs111033290

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036079	SCV000059731	likely pathogenic	Rare genetic deafness	2007-08-22	criteria provided, single submitter	clinical testing
GeneDx	RCV000519124	SCV000616804	likely pathogenic	not provided	2017-11-10	criteria provided, single submitter	clinical testing	The c.2187+1 G>A splice site variant has been previously reported in association with Usher syndrome (Adato et al., 1997). This variant destroys the canonical splice donor site in intron 18, and is expected to cause abnormal gene splicing. The variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). In summary, we consider this variant to be likely pathogenic.
Athena Diagnostics	RCV000519124	SCV001144660	likely pathogenic	not provided	2018-12-07	criteria provided, single submitter	clinical testing	The variant disrupts a canonical splice site, and is therefore predicted to result in the loss of a functional protein. The best available variant frequency is uninformative because it is below the disease allele frequency.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000519124	SCV001582288	pathogenic	not provided	2023-12-14	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 18 of the MYO7A gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MYO7A are known to be pathogenic (PMID: 8900236, 25404053). This variant is present in population databases (rs111033290, gnomAD 0.03%). Disruption of this splice site has been observed in individuals with Usher syndrome type I (PMID: 9382091, 19074810). This variant is also known as IVS18 +1G>A. ClinVar contains an entry for this variant (Variation ID: 43175). 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.
Revvity Omics, Revvity	RCV000519124	SCV002017704	pathogenic	not provided	2021-01-15	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV001003084	SCV002060313	pathogenic	Usher syndrome type 1	2022-01-05	criteria provided, single submitter	clinical testing	NM_000260.3(MYO7A):c.2187+1G>A is a canonical splice variant classified as pathogenic in the context of MYO7A-related disorders. c.2187+1G>A has been observed in cases with relevant disease (PMID: 9382091, 19074810, 33111345). Functional assessments of this variant are not available in the literature. c.2187+1G>A has been observed in population frequency databases (gnomAD: ASJ 0.04%). In summary, NM_000260.3(MYO7A):c.2187+1G>A is a canonical splice variant in a gene where loss of function is a known mechanism of disease, is predicted to disrupt protein function, and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Fulgent Genetics, Fulgent Genetics	RCV002477079	SCV002784652	likely pathogenic	Autosomal dominant nonsyndromic hearing loss 11; Autosomal recessive nonsyndromic hearing loss 2; Usher syndrome type 1	2021-09-21	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000519124	SCV005199440	pathogenic	not provided	2022-06-08	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004786305	SCV005399175	pathogenic	Nonsyndromic genetic hearing loss	2020-05-21	criteria provided, single submitter	clinical testing	A heterozygous canonical splice site variant was identified, NM_000260.3(MYO7A):c.2187+1G>A in intron 18 of 48 of the MYO7A gene. The nucleotide at this position has very high conservation (PhyloP, UCSC). In silico software predicts this variant to cause aberrant splicing (NetGene2, NNSPLICE, Human Splicing Finder), however, , RNA studies are required to determine if splicing is altered. The variant is present in the gnomAD population database at a frequency of 0.002% (5 heterozygotes; 0 homozygotes). The variant has previously been reported as pathogenic in patients with autosomal recessive Usher syndrome (ClinVar, Adato, A. et al. (1997), Jacobson, S. et al. (2009), Jiang, L. et al. (2015)). A different variant in the same splice site (c.2187+1G>T) has also been shown to cause Usher syndrome (Khalaileh, A. et al. (2018)). A heterozygous canonical splice site variant was identified, NM_000260.3(MYO7A):c.2187+1G>A in intron 18 of 48 of the MYO7A gene. The nucleotide at this position has very high conservation (PhyloP, UCSC). In silico software predicts this variant to cause aberrant splicing (NetGene2, NNSPLICE, Human Splicing Finder). The variant is present in the gnomAD population database at a frequency of 0.002% (5 heterozygotes; 0 homozygotes). The variant has previously been reported as pathogenic in patients with Usher syndrome (ClinVar, Adato, A. et al. (1997), Jacobson, S. et al. (2009), Jiang, L. et al. (2015)). A different variant in the same splice site (c.2187+1G>T) has also been shown to cause Usher syndrome (Khalaileh, A. et al. (2018)). Subsequent analysis of parental samples indicated that this variant was maternally inherited. Based on information available at the time of curation, this variant has been classified as PATHOGENIC. Based on information available at the time of curation, this variant has been classified as PATHOGENIC.
Sharon lab, Hadassah-Hebrew University Medical Center	RCV001003084	SCV001161143	pathogenic	Usher syndrome type 1	2019-06-23	no assertion criteria provided	research