NM_016239.4(MYO15A):c.10247CCT[1] (p.Ser3417del) AND Autosomal recessive nonsyndromic hearing loss 3

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Sep 1, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001089558.4

Allele description [Variation Report for NM_016239.4(MYO15A):c.10247CCT[1] (p.Ser3417del)]

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

Gene:

MYO15A:myosin XVA [Gene - OMIM - HGNC]

Variant type:

Microsatellite

Cytogenetic location:

17p11.2

Genomic location:

Preferred name:

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

HGVS:

NC_000017.11:g.18172187CCT[1]
NC_000017.11:g.18172187_18172189CCT[1]
NG_011634.2:g.68482CCT[1]
NM_016239.4:c.10247CCT[1]MANE SELECT
NM_016239.4:c.10250_10252del
NP_057323.3:p.Ser3417del
NC_000017.10:g.18075499_18075501del
NC_000017.10:g.18075501CCT[1]
NC_000017.11:g.18172190_18172192delCCT
NM_016239.3:c.10250_10252del
NM_016239.3:c.10250_10252delCCT
NM_016239.4:c.10250_10252delMANE SELECT
NM_016239.4:c.10250_10252delCCTMANE SELECT

Protein change:

S3417del

Links:

dbSNP: rs760069953

NCBI 1000 Genomes Browser:

rs760069953

Molecular consequence:

NM_016239.4:c.10247CCT[1] - inframe_deletion - [Sequence Ontology: SO:0001822]

Observations:

Condition(s)

Name:: Autosomal recessive nonsyndromic hearing loss 3
Synonyms:: NEUROSENSORY NONSYNDROMIC RECESSIVE DEAFNESS 3; Deafness, autosomal recessive 3
Identifiers:: MONDO: MONDO:0010860; MedGen: C1838263; Orphanet: 90636; OMIM: 600316

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001244795	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Aug 22, 2017)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001984912	Molecular Diagnosis Center for Deafness	criteria provided, single submitter (ClinGen HL ACMG Specifications v1)	Pathogenic	maternal	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002572658	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Sep 1, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25792667, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001244795

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Aug 22, 2017)

unknown

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV001984912

Molecular Diagnosis Center for Deafness

criteria provided, single submitter

(ClinGen HL ACMG Specifications v1)

Pathogenic

maternal

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV002572658

3billion

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Sep 1, 2022)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	1	not provided	clinical testing
not provided	maternal	unknown	2	2	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Expert specification of the ACMG/AMP variant interpretation guidelines for genetic hearing loss.

Oza AM, DiStefano MT, Hemphill SE, Cushman BJ, Grant AR, Siegert RK, Shen J, Chapin A, Boczek NJ, Schimmenti LA, Murry JB, Hasadsri L, Nara K, Kenna M, Booth KT, Azaiez H, Griffith A, Avraham KB, Kremer H, Rehm HL, Amr SS, Abou Tayoun AN; et al.

Hum Mutat. 2018 Nov;39(11):1593-1613. doi: 10.1002/humu.23630.

PubMed [citation]

PMID:: 30311386
PMCID:: PMC6188673

Mutations in the MYO15A gene are a significant cause of nonsyndromic hearing loss: massively parallel DNA sequencing-based analysis.

Miyagawa M, Nishio SY, Hattori M, Moteki H, Kobayashi Y, Sato H, Watanabe T, Naito Y, Oshikawa C, Usami S.

Ann Otol Rhinol Laryngol. 2015 May;124 Suppl 1:158S-68S. doi: 10.1177/0003489415575058. Epub 2015 Mar 19.

PubMed [citation]

PMID:: 25792667

See all PubMed Citations (3)

Details of each submission

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV001244795.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

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).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Molecular Diagnosis Center for Deafness, SCV001984912.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	maternal	unknown	not provided	not provided	not provided		2	not provided	2	not provided

From 3billion, SCV002572658.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (2)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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