Submissions for variant NM_004999.4(MYO6):c.475G>A (p.Glu159Lys)

gnomAD frequency: 0.00026  dbSNP: rs201507590

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hearing Loss Variant Curation Expert Panel	RCV000710350	SCV000840548	benign	Nonsyndromic genetic hearing loss	2018-09-20	reviewed by expert panel	curation	The filtering allele frequency of the p.Glu159Lys variant in the MYO6 gene is 0.7% for Ashkenazi Jewish chromosomes in the Genome Aggregation Database (91/10146 with 95%CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal dominant hearing loss variants (BA1).
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000038312	SCV000061981	uncertain significance	not specified	2016-01-29	criteria provided, single submitter	clinical testing	The p.Glu159Lys variant in MYO6 has been identified by our laboratory in 1 indiv idual with hearing loss and in 38/66510 European chromosomes by the Exome Aggreg ation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs201507590). Comp utational prediction tools and conservation analysis do not provide strong suppo rt for or against an impact to the protein. In summary, the clinical significanc e of the p.Glu159Lys variant is uncertain.
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000038312	SCV000297180	uncertain significance	not specified	2015-10-30	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000315358	SCV000465362	likely benign	Autosomal dominant nonsyndromic hearing loss 22	2018-01-12	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.
Illumina Laboratory Services, Illumina	RCV000353874	SCV000465363	uncertain significance	Autosomal recessive nonsyndromic hearing loss 37	2018-01-12	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.
GeneDx	RCV000766700	SCV000529313	uncertain significance	not provided	2023-01-31	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Classified as benign by the ClinGen Hearing Loss Expert Panel (ClinVar SCV000840548.3; Oza et al., 2018)
Invitae	RCV000766700	SCV002364817	benign	not provided	2023-10-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002513501	SCV003692630	uncertain significance	Inborn genetic diseases	2022-06-10	criteria provided, single submitter	clinical testing	The c.475G>A (p.E159K) alteration is located in exon 6 (coding exon 5) of the MYO6 gene. This alteration results from a G to A substitution at nucleotide position 475, causing the glutamic acid (E) at amino acid position 159 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
CeGaT Center for Human Genetics Tuebingen	RCV000766700	SCV004185370	likely benign	not provided	2023-11-01	criteria provided, single submitter	clinical testing	MYO6: PP3, BS1