Submissions for variant NM_004999.4(MYO6):c.1025C>T (p.Ala342Val)

gnomAD frequency: 0.00128  dbSNP: rs145564837

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hearing Loss Variant Curation Expert Panel	RCV000787984	SCV000927007	benign	Nonsyndromic genetic hearing loss	2019-03-25	reviewed by expert panel	curation	The filtering allele frequency of the p.Ala342Val variant in the MYO6 gene is 0.21% for European (non-Finnish) chromosomes by gnomAD (304/129090 with 95% CI), and one homozygous European (Finnish) individual, 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). The REVEL computational prediction analysis tool produced a score of 0.905, however, this information is not predictive of pathogenicity on its own and is not considered in conflict with evidence that supports a benign interpretation. In summary, the HL EP classified this variant as benign. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BA1.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000038280	SCV000061949	likely benign	not specified	2017-12-21	criteria provided, single submitter	clinical testing	p.Ala342Val in exon 11 of MYO6: This variant is not expected to have clinical si gnificance because it has been identified in 0.24% (304/126610) of Non-Finnish E uropean chromosomes and 0.16% (42/25786) of Finnish chromosomes including 1 homo zygote by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute. org; dbSNP rs145564837). It has been previously reported by our laboratory in th e heterozygous state in 6 individuals with hearing loss, including 2 with differ ent alternate etiologies. ACMG/AMP criteria applied: BS1_supporting, BP5.
Eurofins Ntd Llc (ga)	RCV000488280	SCV000225350	uncertain significance	not provided	2015-01-30	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000382776	SCV000465372	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	RCV000271910	SCV000465373	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.
CeGaT Center for Human Genetics Tuebingen	RCV000488280	SCV000575488	benign	not provided	2023-06-01	criteria provided, single submitter	clinical testing	MYO6: PP3, BS1, BS2
Athena Diagnostics	RCV000488280	SCV001144691	likely benign	not provided	2019-03-21	criteria provided, single submitter	clinical testing
Invitae	RCV000488280	SCV001617399	likely benign	not provided	2023-12-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000488280	SCV001776351	likely benign	not provided	2020-06-04	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 27068579)
PreventionGenetics, part of Exact Sciences	RCV004534809	SCV004741599	likely benign	MYO6-related disorder	2019-10-29	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000488280	SCV001928583	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000488280	SCV001957429	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000488280	SCV001967273	likely benign	not provided		no assertion criteria provided	clinical testing