Submissions for variant NM_016239.4(MYO15A):c.10247CCT[1] (p.Ser3417del)

dbSNP: rs760069953

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001089558	SCV001244795	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 3	2017-08-22	criteria provided, single submitter	clinical testing	A heterozygous in-frame deletion variant was identified in exon 64 of MYO15A, NM_016239.3(MYO15A):c.10250_10252delCCT.This deletionresults in the lossof a serineat codon position 3417, NP_057323.3(MYO15A):p.(Ser3417del). The serine at this position has very high conservation (100 vertebrates, UCSC). It is situated in the FERM domain. This variant is present in the gnomAD population database at a frequency of 0.002%. It has not been previously observed in other clinical cases. Based on current information and in association with the NM_016239.3(MYO15A):c.9371dupA deletion variant, this variant has been classified as LIKELY PATHOGENIC.Parental testingindicates the variants are in trans. The presence of these two variants suggests a possible compound heterozygous mode of inheritance which is consistent with autosomal recessive deafness 3.NB: This variant has been reclassified from Class 3A (VUS with high clinical significance)to Class 4 (likely pathogenic).
Molecular Diagnosis Center for Deafness	RCV001089558	SCV001984912	pathogenic	Autosomal recessive nonsyndromic hearing loss 3		criteria provided, single submitter	clinical testing
GeneDx	RCV001759858	SCV001986243	uncertain significance	not provided	2020-09-23	criteria provided, single submitter	clinical testing	In-frame deletion of 1 amino acids in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25792667, 29482514, 31581539, 31827275, 30896630)
3billion	RCV001089558	SCV002572658	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 3	2022-09-01	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.003%). This variant leads to inframe deletion located in a nonrepeat region that it is predicted to change the length of the protein and disrupt normal protein function. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000869466 / PMID: 25792667). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.
Invitae	RCV001759858	SCV004298179	pathogenic	not provided	2024-01-29	criteria provided, single submitter	clinical testing	This variant, c.10250_10252del, results in the deletion of 1 amino acid(s) of the MYO15A protein (p.Ser3417del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs760069953, gnomAD 0.04%). This variant has been observed in individual(s) with deafness (PMID: 25792667, 29482514, 30896630, 34265623, 35346193). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as c.10249_10251delTCC (p.F3417del) or c.10245_10247delCTC. ClinVar contains an entry for this variant (Variation ID: 869466). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV004017785	SCV004847413	pathogenic	Rare genetic deafness	2024-01-10	criteria provided, single submitter	clinical testing	The p.Ser3417del variant in MYO15A has been reported in >15 compound heterozygous or homozygous individuals with hearing loss and segregated with disease in at least 4 affected individuals from 3 families (Miyagawa 2015 PMID: 25792667, Chang 2018 PMID: 29482514, Sun 2019 PMID: 30896630, Xu 2020 PMID: 32802042, Downie 2020 PMID: 31827275, Liang 2021 PMID: 34265623, Chen 2022 PMID: 34974475, Fu 2022 PMID: 35346193, Kim 2022 PMID: 35853923, Ma 2023 PMID: 36597107). It has also been identified in 0.027% (12/44898) of East Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.4.0.0). This variant has also been reported in ClinVar (Variation ID 869466). This variant is a deletion of 1 amino acid at position 3417 and is not predicted to alter the protein reading-frame. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hearing loss. ACMG/AMP Criteria applied: PM3_VeryStrong, PP1_Strong, PM4_Supporting.