NM_017534.6(MYH2):c.4442G>A (p.Arg1481His) AND Myopathy, proximal, and ophthalmoplegia

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Dec 9, 2023
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:: RCV000794881.9

Allele description [Variation Report for NM_017534.6(MYH2):c.4442G>A (p.Arg1481His)]

NM_017534.6(MYH2):c.4442G>A (p.Arg1481His)

Genes:

LOC126862500:BRD4-independent group 4 enhancer GRCh37_chr17:10427829-10429028 [Gene]
MYH2:myosin heavy chain 2 [Gene - OMIM - HGNC]
MYHAS:myosin heavy chain gene cluster antisense RNA [Gene - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

17p13.1

Genomic location:

Preferred name:

NM_017534.6(MYH2):c.4442G>A (p.Arg1481His)

HGVS:

NC_000017.11:g.10525546C>T
NG_013014.1:g.29155G>A
NM_001100112.2:c.4442G>A
NM_017534.5:c.4442G>A
NM_017534.6:c.4442G>AMANE SELECT
NP_001093582.1:p.Arg1481His
NP_060004.3:p.Arg1481His
NC_000017.10:g.10428863C>T
NM_017534.6:c.4442G>A

Protein change:

R1481H

Links:

dbSNP: rs199751037

NCBI 1000 Genomes Browser:

rs199751037

Molecular consequence:

NM_001100112.2:c.4442G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_017534.6:c.4442G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Myopathy, proximal, and ophthalmoplegia (CMYP6)
Synonyms:: Inclusion body myopathy 3; Myopathy with congenital joint contractures, ophthalmoplegia, and rimmed vacuoles; Inclusion body myopathy autosomal dominant; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0011577; MedGen: C1854106; Orphanet: 363677; Orphanet: 79091; OMIM: 605637

Recent activity

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voltage-dependent L-type calcium channel subunit alpha-1C isoform X33 [Homo sapi...
voltage-dependent L-type calcium channel subunit alpha-1C isoform X33 [Homo sapiens]
gi|767971484|ref|XP_011519325.1|

Protein
TMEM150A transmembrane protein 150A [Homo sapiens]
TMEM150A transmembrane protein 150A [Homo sapiens]
Gene ID:129303

Gene
Microbe sample from Vibrio cyclitrophicus
Microbe sample from Vibrio cyclitrophicus

biosample
SRA Links for BioSample (Select 14854770) (1)
SRA
LOC4335304 [Oryza sativa Japonica Group]
LOC4335304 [Oryza sativa Japonica Group]
Gene ID:4335304

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000934315	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 9, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003809471	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Dec 1, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004704491	Human Genetics Bochum, Ruhr University Bochum	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Apr 18, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000934315

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Dec 9, 2023)

germline

clinical testing

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

SCV003809471

Revvity Omics, Revvity

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Dec 1, 2023)

germline

clinical testing

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

SCV004704491

Human Genetics Bochum, Ruhr University Bochum

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Apr 18, 2023)

germline

clinical testing

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

Help

Summary from all submissions

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

Citations

PubMed

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):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Invitae, SCV000934315.5

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

Description

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1481 of the MYH2 protein (p.Arg1481His). This variant is present in population databases (rs199751037, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with MYH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 641606). 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 MYH2 protein function with a positive predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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

From Revvity Omics, Revvity, SCV003809471.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	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	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Human Genetics Bochum, Ruhr University Bochum, SCV004704491.1

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

Description

ACMG criteria used to clasify this variant: PP3_MOD

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

Last Updated: May 1, 2024

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