rs121912560

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PP3_StrongPP5_Very_Strong

The NM_004999.4(MYO6):c.737A>G(p.His246Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000315 in 1,461,670 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000031 ( 0 hom. )

Consequence

MYO6
NM_004999.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 8.92

Publications

19 publications found

Variant links:

Genes affected

MYO6 (HGNC:7605): (myosin VI) This gene encodes a reverse-direction motor protein that moves toward the minus end of actin filaments and plays a role in intracellular vesicle and organelle transport. The protein consists of a motor domain containing an ATP- and an actin-binding site and a globular tail which interacts with other proteins. This protein maintains the structural integrity of inner ear hair cells and mutations in this gene cause non-syndromic autosomal dominant and recessive hearing loss. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jul 2014]

MYO6 Gene-Disease associations (from GenCC):

autosomal dominant nonsyndromic hearing loss 22
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia
nonsyndromic genetic hearing loss
Inheritance: AD, AR Classification: DEFINITIVE, MODERATE Submitted by: ClinGen, G2P
autosomal recessive nonsyndromic hearing loss 37
Inheritance: AR Classification: STRONG, MODERATE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics
autosomal dominant nonsyndromic hearing loss
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
progressive sensorineural hearing loss-hypertrophic cardiomyopathy syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

MYO6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.966

PP5

Variant 6-75841299-A-G is Pathogenic according to our data. Variant chr6-75841299-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 8581.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO6	NM_004999.4 link	c.737A>G	p.His246Arg	missense_variant	Exon 9 of 35	ENST00000369977.8	NP_004990.3	Q9UM54-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO6	ENST00000369977.8 link	c.737A>G	p.His246Arg	missense_variant	Exon 9 of 35	1	NM_004999.4	ENSP00000358994.3		Q9UM54-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

250992

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000315

AC:

AN:

1461670

Hom.:

Cov.:

AF XY:

0.0000261

AC XY:

AN XY:

727146

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39684

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53374

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000396

AC:

AN:

1111880

Other (OTH)

AF:

0.00

AC:

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000968

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

May 29, 2025

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at 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: 18212818, 18348273, 29044474, 29224747, 34662886, 15060111, 36788145) -

Nov 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 246 of the MYO6 protein (p.His246Arg). This variant is present in population databases (rs121912560, gnomAD 0.003%). This missense change has been observed in individual(s) with autosomal dominant deafness (PMID: 15060111). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 8581). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt MYO6 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

Progressive sensorineural hearing loss-hypertrophic cardiomyopathy syndrome

Pathogenic:1

Apr 01, 2004

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Rare genetic deafness

Pathogenic:1

Jul 30, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.His246Arg variant in MYO6 has been reported in one individual with progres sive, post-lingual sensorineural hearing loss and left ventricular hypertrophy ( LVH), and it segregated with hearing loss in 9 affected relatives (Mohiddin 2004 ). Two family members (ages 12 and 28 years) carried the variant but did not hav e hearing loss, which may reflect reduced penetrance or variable onset. Alternat ively, of the 11 family members that carried the p.His246Arg variant, only 4 ind ividuals presented with cardiac hypertrophy, while another 3 family members were reported to have an abnormal ECG. While this could also indicate reduced penetr ance of LVH, given that no other variant in the MYO6 gene has been associated wi th cardiac hypertrophy, it is possible that the LVH in the family is caused by a n unrelated etiology. Of note, one family member who did not carry the variant a nd did not have sensorineural hearing loss was reported to have LVH which indica tes that this MYO6 variant does not segregate with that manifestation; however, the authors attributed this individual's cardiac features to valvar and ischaemi c disease. The variant was absent in population databases. In summary, although additional studies are required to fully establish its clinical significance, th is variant is likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Pathogenic

0.50

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.90

D;.;.;.;D;D

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.95

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

D;.;D;D;D;D

M_CAP

Pathogenic

0.43

MetaRNN

Pathogenic

0.97

D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.5

.;H;H;H;.;.

PhyloP100

8.9

PrimateAI

Pathogenic

0.89

PROVEAN

Pathogenic

-7.8

D;D;D;.;D;.

REVEL

Pathogenic

0.93

Sift

Pathogenic

0.0

D;D;D;.;D;.

Sift4G

Pathogenic

0.0

D;D;D;D;D;D

Polyphen

1.0, 0.99

.;D;D;D;.;.

Vest4

1.0

MVP

0.96

MPC

0.32

ClinPred

1.0

GERP RS

5.3

gMVP

0.93

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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rs121912560

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over