VCV001120059.36 - ClinVar

NM_016239.4(MYO15A):c.4252G>A (p.Gly1418Arg)

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Pathogenic/Likely pathogenic
Pathogenic (4); Likely pathogenic (2)

6 out of 6 submissions contributed to this classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_016239.4(MYO15A):c.4252G>A (p.Gly1418Arg)

Variation ID: 1120059 Accession: VCV001120059.36

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 17p11.2 17: 18132498 (GRCh38) [ NCBI UCSC ] 17: 18035812 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	May 29, 2021	Feb 15, 2026	May 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_016239.4:c.4252G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_057323.3:p.Gly1418Arg	missense
NC_000017.11:g.18132498G>A
NC_000017.10:g.18035812G>A
NG_011634.2:g.28793G>A

Protein change

G1418R

Other names

Canonical SPDI

NC_000017.11:18132497:G:A

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Exome Aggregation Consortium (ExAC) 0.00001

The Genome Aggregation Database (gnomAD) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00001

Links

ClinGen: CA8423831 dbSNP: rs753790346 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
MYO15A		Gene associated with autosomal recessive phenotype	Not yet evaluated	GRCh38 GRCh37	3847	3998

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Rare genetic deafness	Likely pathogenic (1)	criteria provided, single submitter	Jun 19, 2023	RCV001449688.5
Autosomal recessive nonsyndromic hearing loss 3	Pathogenic/Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Jan 6, 2024	RCV002224976.2
not provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Dec 8, 2023	RCV001572126.11
Hearing loss, autosomal recessive	Pathogenic (1)	criteria provided, single submitter	May 1, 2024	RCV004719041.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	Expand all rows Collapse all rows Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely Pathogenic (Jun 19, 2023) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Rare genetic deafness	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV001652940.2 First in ClinVar: May 29, 2021 Last updated: Apr 20, 2024	Publications: PubMed (2) PubMed: 25373420‚ 30953472 Comment: show The p.Gly1418Arg variant in MYO15A has been previously reported in three compound heterozygous individuals with congenital profound hearing loss (Park 2014 PMID: 25373420, Zhang 2019 PMID: 30953472, LMM internal data). This variant has been identified in 0.0065% (1/15280) of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2); however, this frequency is low enough to be consistent with a recessive allele frequency. Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive hearing loss. ACMG/AMP Criteria applied: PM3_Strong, PM2_Supporting, PP3. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (-) C Contributing to aggregate classification	criteria provided, single submitter (ClinGen HL ACMG Specifications v1)	Autosomal recessive nonsyndromic hearing loss 3	Molecular Diagnosis Center for Deafness Accession: SCV001984899.1 First in ClinVar: Apr 29, 2022 Last updated: Apr 29, 2022	Observation: 1 Collection method: clinical testing Allele origin: maternal Affected status: unknown more Observation 1 Collection method: clinical testing Allele origin: maternal Affected status: unknown Number of individuals with the variant: 1

Pathogenic (Dec 08, 2023) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	not provided	GeneDx Accession: SCV001796710.4 First in ClinVar: Aug 21, 2021 Last updated: Sep 29, 2024	Comment: show Not observed at a significant frequency in large population cohorts (gnomAD); 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: 34416374, 25373420, 30953472, 35346193) (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Likely pathogenic (Jan 06, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Autosomal recessive nonsyndromic hearing loss 3	Fulgent Genetics, Fulgent Genetics Accession: SCV005645966.1 First in ClinVar: Jan 25, 2025 Last updated: Jan 25, 2025	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

PATHOGENIC (May 01, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ClinGen HL ACMG Specifications v1)	Hearing loss, autosomal recessive	Laboratory of Human Genetics, Universidade de São Paulo Accession: SCV005324776.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024	Comment: show The MYO15A NM_016239.3:c.4252G>A variant has extremely low frequency in gnomAD population databases, For recessive disorders, detected in trans with a pathogenic variant, or in a homozygous or compound heterozygous state in affected cases (PM3), computational prediction tools unanimously support a deleterious effect on the gene (PP3). In this report it was found in trans with c.8080C>A, in two affected siblings born from unrelated couple. (less) Observation: 1 Collection method: research Allele origin: maternal Affected status: yes more Observation 1 Collection method: research Allele origin: maternal Affected status: yes Number of individuals with the variant: 2 Clinical Features: Hearing impairment (present) Test name: whole exome sequencing Family history: yes

Pathogenic (Nov 21, 2023) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	not provided	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002186122.5 First in ClinVar: Mar 28, 2022 Last updated: Feb 15, 2026	Publications: PubMed (2) PubMed: 25373420‚ 30953472 Comment: show This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1418 of the MYO15A protein (p.Gly1418Arg). This variant is present in population databases (rs753790346, gnomAD 0.003%). This missense change has been observed in individual(s) with autosomal recessive deafness (PMID: 25373420, 30953472; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 1120059). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MYO15A protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Comment:

The p.Gly1418Arg variant in MYO15A has been previously reported in three compound heterozygous individuals with congenital profound hearing loss (Park 2014 PMID: 25373420, Zhang 2019 PMID: 30953472, LMM internal data). This variant has been identified in 0.0065% (1/15280) of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2); however, this frequency is low enough to be consistent with a recessive allele frequency. Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive hearing loss. ACMG/AMP Criteria applied: PM3_Strong, PM2_Supporting, PP3.

Comment:

Not observed at a significant frequency in large population cohorts (gnomAD); 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: 34416374, 25373420, 30953472, 35346193)

Comment:

The MYO15A NM_016239.3:c.4252G>A variant has extremely low frequency in gnomAD population databases, For recessive disorders, detected in trans with a pathogenic variant, or in a homozygous or compound heterozygous state in affected cases (PM3), computational prediction tools unanimously support a deleterious effect on the gene (PP3). In this report it was found in trans with c.8080C>A, in two affected siblings born from unrelated couple.

Comment:

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1418 of the MYO15A protein (p.Gly1418Arg). This variant is present in population databases (rs753790346, gnomAD 0.003%). This missense change has been observed in individual(s) with autosomal recessive deafness (PMID: 25373420, 30953472; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 1120059). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MYO15A protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Genotype-phenotype correlation analysis of MYO15A variants in autosomal recessive non-syndromic hearing loss.	Zhang J	BMC medical genetics	2019	PMID: 30953472
Exploration of molecular genetic etiology for Korean cochlear implantees with severe to profound hearing loss and its implication.	Park JH	Orphanet journal of rare diseases	2014	PMID: 25373420

Text-mined citations for rs753790346 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Apr 13, 2026