Submissions for variant NM_000260.4(MYO7A):c.2618G>A (p.Arg873Gln)

gnomAD frequency: 0.00002  dbSNP: rs1052032

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036093	SCV000059745	uncertain significance	not specified	2011-03-31	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The Arg873Gln varia nt in MYO7A has not been reported in the literature nor previously identified by our laboratory; however, it is recorded in dbSNP (rs1052032 - 1/188 Caucasian p robands). This residue is conserved across species and computational analyses (P olyPhen2, SIFT) suggest that the Arg873Gln variant may impact the protein. Howev er, this information is not predictive enough to assume pathogenicity. It should be noted that this lab has only sequenced the MYO7A in 34 Hispanic probands and no Hispanic healthy controls. In addition, healthy control information is unava ilable from either public databases or scientific literature, such that the full spectrum of benign variation has not yet been defined for this population. Futu re analysis could reveal that the Arg873Gln variant is common in this population and therefore unlikely to be pathogenic. In summary, the clinical significance of this variant cannot be determined with certainty at this time.
Illumina Laboratory Services, Illumina	RCV000375210	SCV000374305	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.
Illumina Laboratory Services, Illumina	RCV000278350	SCV000374306	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	RCV000317296	SCV000374307	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.
Invitae	RCV001056783	SCV001221247	uncertain significance	not provided	2023-12-27	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 873 of the MYO7A protein (p.Arg873Gln). This variant is present in population databases (rs1052032, gnomAD 0.06%). This variant has not been reported in the literature in individuals affected with MYO7A-related conditions. ClinVar contains an entry for this variant (Variation ID: 43189). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MYO7A protein function. 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	RCV001056783	SCV001767832	uncertain significance	not provided	2022-12-28	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Fulgent Genetics, Fulgent Genetics	RCV002482970	SCV002787699	uncertain significance	Autosomal dominant nonsyndromic hearing loss 11; Autosomal recessive nonsyndromic hearing loss 2; Usher syndrome type 1	2021-08-26	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002513369	SCV003688120	uncertain significance	Inborn genetic diseases	2022-10-03	criteria provided, single submitter	clinical testing	The c.2618G>A (p.R873Q) alteration is located in exon 22 (coding exon 21) of the MYO7A gene. This alteration results from a G to A substitution at nucleotide position 2618, causing the arginine (R) at amino acid position 873 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Natera, Inc.	RCV001835642	SCV002086631	uncertain significance	Usher syndrome type 1B	2020-03-04	no assertion criteria provided	clinical testing