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NM_004999.4(MYO6):c.737A>G (p.His246Arg) AND not provided

Germline classification:
Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:
Jan 3, 2024
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:
RCV001582473.6

Allele description [Variation Report for NM_004999.4(MYO6):c.737A>G (p.His246Arg)]

NM_004999.4(MYO6):c.737A>G (p.His246Arg)

Gene:
MYO6:myosin VI [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
6q14.1
Genomic location:
Preferred name:
NM_004999.4(MYO6):c.737A>G (p.His246Arg)
HGVS:
  • NC_000006.12:g.75841299A>G
  • NG_009934.2:g.97107A>G
  • NM_001300899.2:c.737A>G
  • NM_001368136.1:c.737A>G
  • NM_001368137.1:c.737A>G
  • NM_001368138.1:c.722A>G
  • NM_001368139.1:c.737A>G
  • NM_001368140.1:c.737A>G
  • NM_001368865.1:c.737A>G
  • NM_001368866.1:c.737A>G
  • NM_004999.4:c.737A>GMANE SELECT
  • NP_001287828.1:p.His246Arg
  • NP_001355065.1:p.His246Arg
  • NP_001355066.1:p.His246Arg
  • NP_001355067.1:p.His241Arg
  • NP_001355068.1:p.His246Arg
  • NP_001355069.1:p.His246Arg
  • NP_001355794.1:p.His246Arg
  • NP_001355795.1:p.His246Arg
  • NP_004990.3:p.His246Arg
  • LRG_438t1:c.737A>G
  • LRG_438:g.97107A>G
  • LRG_438p1:p.His246Arg
  • NC_000006.11:g.76551016A>G
  • NG_009934.1:g.97108A>G
  • NM_004999.3:c.737A>G
  • NR_160538.1:n.969A>G
  • NR_160539.1:n.1069A>G
Protein change:
H241R; HIS246ARG
Links:
OMIM: 600970.0005; dbSNP: rs121912560
NCBI 1000 Genomes Browser:
rs121912560
Molecular consequence:
  • NM_001300899.2:c.737A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001368136.1:c.737A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001368137.1:c.737A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001368138.1:c.722A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001368139.1:c.737A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001368140.1:c.737A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001368865.1:c.737A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001368866.1:c.737A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_004999.4:c.737A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NR_160538.1:n.969A>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_160539.1:n.1069A>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Synonyms:
none provided
Identifiers:
MedGen: C3661900

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001813096GeneDx
criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)
Likely pathogenic
(May 1, 2023)
germlineclinical testing

Citation Link,

SCV003017778Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Pathogenic
(Jan 3, 2024)
germlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Novel association of hypertrophic cardiomyopathy, sensorineural deafness, and a mutation in unconventional myosin VI (MYO6).

Mohiddin SA, Ahmed ZM, Griffith AJ, Tripodi D, Friedman TB, Fananapazir L, Morell RJ.

J Med Genet. 2004 Apr;41(4):309-14. No abstract available.

PubMed [citation]
PMID:
15060111
PMCID:
PMC1735721

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Details of each submission

From GeneDx, SCV001813096.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

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: 15060111, 18212818, 18348273, 29044474, 29224747, 27535533, 34662886)

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV003017778.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

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). 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 MYO6 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Feb 28, 2024