Submissions for variant NM_016239.4(MYO15A):c.3622C>T (p.Arg1208Cys)

gnomAD frequency: 0.00063  dbSNP: rs201618718

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000213556	SCV000272093	uncertain significance	not specified	2018-04-11	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The p.Arg1208Cys va riant in MYO15A has been previously identified by our laboratory in two individu als with hearing loss; however, a variant in trans was not identied in either of these individuals. This variant has been identified in 0.2% (60/30752) of South Asian chromosomes and 0.1% (132/126234) of European chromosomes by the Genome A ggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs201618718 ). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Computational prediction tools and conservation analysis do not provide strong support for or against an impac t to the protein; however, arginine at position 1208 is not conserved and severa l evolutionarily distant species carry a cysteine, raising the possibility that this change may be tolerated. In summary, while the clinical significance of the p.Arg1208Cys variant is uncertain, its lack of conservation suggests that it is more likely to be benign. ACMG/AMP Criteria applied: BP4
Illumina Laboratory Services, Illumina	RCV001126421	SCV001285616	uncertain significance	Autosomal recessive nonsyndromic hearing loss 3	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.
Baylor Genetics	RCV001126421	SCV001526616	uncertain significance	Autosomal recessive nonsyndromic hearing loss 3	2018-02-08	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
GeneDx	RCV001589134	SCV001814527	uncertain significance	not provided	2024-09-20	criteria provided, single submitter	clinical testing	Identified with a second MYO15A variant via carrier screening of parents with two affected children with hearing impairment, as well as Van Maldergem syndrome and co-occurring FAT4 variants (PMID: 37551355); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 36703223, 39038432, 37551355)
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV001126421	SCV001984462	uncertain significance	Autosomal recessive nonsyndromic hearing loss 3	2020-11-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001589134	SCV002404148	benign	not provided	2024-12-12	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV001589134	SCV004224324	uncertain significance	not provided	2022-08-30	criteria provided, single submitter	clinical testing	BS1_supporting