Submissions for variant NM_000260.4(MYO7A):c.2489G>A (p.Arg830His)

gnomAD frequency: 0.00004  dbSNP: rs371029653

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000365276	SCV000374296	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	RCV000395526	SCV000374297	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	RCV000307060	SCV000374298	likely benign	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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Counsyl	RCV000675124	SCV000800693	uncertain significance	Autosomal recessive nonsyndromic hearing loss 2; Usher syndrome type 1	2018-04-06	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000765014	SCV000896198	uncertain significance	Autosomal dominant nonsyndromic hearing loss 11; Autosomal recessive nonsyndromic hearing loss 2; Usher syndrome type 1	2018-10-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000171199	SCV001415477	uncertain significance	not provided	2022-09-01	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 830 of the MYO7A protein (p.Arg830His). This variant is present in population databases (rs371029653, gnomAD 0.02%). This missense change has been observed in individual(s) with autosomal recessive hearing loss (PMID: 27766948). ClinVar contains an entry for this variant (Variation ID: 191024). 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) performed at Invitae indicates that this missense variant is expected to disrupt MYO7A protein function. 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	RCV000171199	SCV001805670	uncertain significance	not provided	2020-12-07	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 32884365, 27766948)
Genome-Nilou Lab	RCV000307060	SCV001806085	likely benign	Autosomal dominant nonsyndromic hearing loss 11	2021-07-14	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000365276	SCV001806086	uncertain significance	Autosomal recessive nonsyndromic hearing loss 2	2021-07-14	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000395526	SCV001806087	uncertain significance	Usher syndrome type 1	2021-07-14	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000395526	SCV004805726	likely benign	Usher syndrome type 1	2024-03-29	criteria provided, single submitter	clinical testing
Laboratory of Prof. Karen Avraham, Tel Aviv University	RCV000365276	SCV005073774	pathogenic	Autosomal recessive nonsyndromic hearing loss 2	2024-06-03	criteria provided, single submitter	research	Likely pathogenic by Deafness Variation Database and Pathogenic based on PMID: 26763877
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000171199	SCV000221396	likely pathogenic	not provided		flagged submission	research
Natera, Inc.	RCV001831992	SCV002086625	uncertain significance	Usher syndrome type 1B	2020-01-16	no assertion criteria provided	clinical testing