Submissions for variant NM_000260.4(MYO7A):c.2282+5G>A

gnomAD frequency: 0.00033  dbSNP: rs540145750

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000353496	SCV000374276	uncertain significance	Autosomal recessive nonsyndromic hearing loss 2	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000268157	SCV000374277	uncertain significance	Usher syndrome type 1	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000304617	SCV000374278	uncertain significance	Autosomal dominant nonsyndromic hearing loss 11	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000611667	SCV000711155	uncertain significance	not specified	2017-08-03	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The c.2282+5G>A var iant in MYO7A has not been previously reported in individuals with hearing loss, but has been identified in 0.18% (45/24682) of Finnish chromosomes and 0.03% (9 0/260052) of all chromosomes by the Genome Aggregation Database (gnomAD, http:// gnomad.broadinstitute.org; dbSNP rs540145750). Although this variant has been se en in the general population, its frequency is not high enough to rule out a pat hogenic role. This variant is located in the 5' splice region. Computational too ls do not suggest an impact to splicing. However, this information is not predic tive enough to rule out pathogenicity. In summary, while the clinical significan ce of the c.2282+5G>A variant is uncertain, its frequency in the general populat ion suggests that it is more likely to be benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001245741	SCV001419046	uncertain significance	not provided	2024-11-28	criteria provided, single submitter	clinical testing	This sequence change falls in intron 19 of the MYO7A gene. It does not directly change the encoded amino acid sequence of the MYO7A protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs540145750, gnomAD 0.2%). This variant has been observed in individual(s) with MYO7A-related conditions (PMID: 37204857). ClinVar contains an entry for this variant (Variation ID: 306174). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
GeneDx	RCV001245741	SCV001991185	uncertain significance	not provided	2019-06-18	criteria provided, single submitter	clinical testing	In silico analysis, which includes splice predictors and evolutionary conservation, suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Has not been previously published as pathogenic or benign to our knowledge
Natera, Inc.	RCV001276688	SCV001463196	uncertain significance	Usher syndrome type 1B	2020-01-24	no assertion criteria provided	clinical testing