NM_017534.6:c.1792G>A

Variant names:

• chr17-10537338-C-T
• rs1555571267
• NM_017534.6:c.1792G>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_017534.6(MYH2):​c.1792G>A​(p.Glu598Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MYH2 NM_017534.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:4
• Conservation: PhyloP100: 5.03

Genes affected

MYH2 (HGNC:7572): (myosin heavy chain 2) Myosins are actin-based motor proteins that function in the generation of mechanical force in eukaryotic cells. Muscle myosins are heterohexamers composed of 2 myosin heavy chains and 2 pairs of nonidentical myosin light chains. This gene encodes a member of the class II or conventional myosin heavy chains, and functions in skeletal muscle contraction. This gene is found in a cluster of myosin heavy chain genes on chromosome 17. A mutation in this gene results in inclusion body myopathy-3. Multiple alternatively spliced variants, encoding the same protein, have been identified. [provided by RefSeq, Sep 2009]

ENSG00000272736 (HGNC:):

MYHAS (HGNC:50609): (myosin heavy chain gene cluster antisense RNA) Predicted to enable primary miRNA binding activity. Predicted to be involved in response to muscle activity and skeletal muscle fiber development. Predicted to act upstream of or within with a positive effect on gene expression. Predicted to be located in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH2	NM_017534.6	c.1792G>A	p.Glu598Lys	missense_variant	Exon 16 of 40	ENST00000245503.10	NP_060004.3
MYH2	NM_001100112.2	c.1792G>A	p.Glu598Lys	missense_variant	Exon 16 of 40		NP_001093582.1
MYHAS	NR_125367.1	n.168-30199C>T		intron_variant	Intron 2 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH2	ENST00000245503.10	c.1792G>A	p.Glu598Lys	missense_variant	Exon 16 of 40	1	NM_017534.6	ENSP00000245503.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461894 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Myopathy, proximal, and ophthalmoplegia Uncertain:3

Feb 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 598 of the MYH2 protein (p.Glu598Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of autosomal dominant myopathy (Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 499533). 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 not expected to disrupt MYH2 protein function with a negative 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. -

Aug 01, 2019

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 22, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense c.1792G>A (p.Glu598Lys) variant in MYH2 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Glu598Lys variant is absent in gnomAD Exomes. This variant has been submitted to the ClinVar database as Uncertain Significance (multiple submission). Multiple lines of computational evidence (Polyphen - Benign, SIFT - Damaging and MutationTaster - Disease causing) predicts conflicting evidence on protein structure and function for this variant. The reference amino acid at this position on MYH2 gene is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Glu at position 598 is changed to a Lys changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Variant of Uncertain Significance (VUS). The missense c.1792G>A (p.Glu598Lys) variant in MYH2 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Glu598Lys variant is absent in gnomAD Exomes. This variant has been submitted to the ClinVar database as Uncertain Significance (multiple submission). Multiple lines of computational evidence (Polyphen - Benign, SIFT - Damaging and MutationTaster - Disease causing) predicts conflicting evidence on protein structure and function for this variant. The reference amino acid at this position on MYH2 gene is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Glu at position 598 is changed to a Lys changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Variant of Uncertain Significance (VUS). -

MYH2-related disorder Pathogenic:1

Apr 22, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The MYH2 c.1792G>A variant is predicted to result in the amino acid substitution p.Glu598Lys. This variant was found in multiple members of a family that underwent testing for inclusion body myositis; the family was previously the subject of study demonstrating an autosomal dominant mode of inheritance for inclusion body myositis (internal data; Neville et al. 1992. PubMed ID: 1314344). This variant was also shown to segregate in another family with a chronic inflammatory myopathy and suggestive inclusion body myositis (pedigree LGMD2377 in an unpublished dissertation; https://hdl.handle.net/10161/7169). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as likely pathogenic. -

not provided Uncertain:1

Jan 17, 2017

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Benign	0.0011	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.69	.;D;D;.
Eigen	Benign	0.17
Eigen_PC	Benign	0.20
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.78	.;.;T;T
M_CAP	Benign	0.052	D
MetaRNN	Uncertain	0.50	D;D;D;D
MetaSVM	Uncertain	0.059	D
MutationAssessor	Uncertain	2.8	M;M;M;M
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-2.2	N;N;N;.
REVEL	Uncertain	0.35
Sift	Uncertain	0.0080	D;D;D;.
Sift4G	Uncertain	0.046	D;T;T;D
Polyphen		0.0050	.;B;B;.
Vest4		0.27
MutPred		0.54		Gain of methylation at E598 (P = 0.0044);Gain of methylation at E598 (P = 0.0044);Gain of methylation at E598 (P = 0.0044);Gain of methylation at E598 (P = 0.0044);
MVP		0.83
MPC		0.86
ClinPred		0.87	D
GERP RS		5.6
Varity_R		0.52
gMVP		0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555571267; hg19: chr17-10440655;