Submissions for variant NM_016239.4(MYO15A):c.3659G>A (p.Gly1220Glu)

gnomAD frequency: 0.00036  dbSNP: rs201689819

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000219805	SCV000270505	likely benign	not specified	2015-05-14	criteria provided, single submitter	clinical testing	p.Gly1220Glu in exon 3 of MYO15A: This variant is not expected to have clinical significance due to a lack of conservation across species, including mammals. Of note, 3 mammals have a glutamic acid (Glu) at this position despite high nearby amino acid conservation. In addition, computational prediction tools do not sug gest a high likelihood of impact to the protein. It has also been identified in 0.2% (11/6112) of Finnish chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs201689819).
Illumina Laboratory Services, Illumina	RCV000999865	SCV000401125	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.
Eurofins Ntd Llc (ga)	RCV000733672	SCV000861765	uncertain significance	not provided	2018-06-19	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000999865	SCV000885803	uncertain significance	Autosomal recessive nonsyndromic hearing loss 3	2023-08-15	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000733672	SCV001144641	uncertain significance	not provided	2019-04-16	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000733672	SCV001665166	likely benign	not provided	2024-01-24	criteria provided, single submitter	clinical testing
GeneDx	RCV000733672	SCV001764184	likely benign	not provided	2020-01-13	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003955256	SCV004771683	likely benign	MYO15A-related disorder	2023-02-24	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).
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000733672	SCV001550938	uncertain significance	not provided		no assertion criteria provided	clinical testing	The MYO15A p.Gly1220Glu variant was not identified in the literature but was identified in dbSNP (ID: rs201689819), LOVD 3.0, ClinVar (classified as uncertain significance by Illumina, EGL Genetic Diagnostics, ARUP Laboratories and Athena Diagnotics, and as likely benign by Laboratory for Molecular Medicine). The variant was identified in control databases in 132 of 279120 chromosomes (1 homozygous) at a frequency of 0.0004729 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (Finnish) in 47 of 24150 chromosomes (freq: 0.001946), European (non-Finnish) in 77 of 127988 chromosomes (freq: 0.000602), Other in 3 of 7122 chromosomes (freq: 0.000421), African in 4 of 24108 chromosomes (freq: 0.000166) and Latino in 1 of 35332 chromosomes (freq: 0.000028), but was not observed in the Ashkenazi Jewish, East Asian, or South Asian populations. The p.Gly1220 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.