14-23424146-G-T

Position:

• chr14-23424146-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP2

The NM_000257.4(MYH7):​c.2683C>A​(p.Gln895Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,824 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q895H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MYH7 NM_000257.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 1.25

Genes affected

MYH7 (HGNC:7577): (myosin heavy chain 7) Muscle myosin is a hexameric protein containing 2 heavy chain subunits, 2 alkali light chain subunits, and 2 regulatory light chain subunits. This gene encodes the beta (or slow) heavy chain subunit of cardiac myosin. It is expressed predominantly in normal human ventricle. It is also expressed in skeletal muscle tissues rich in slow-twitch type I muscle fibers. Changes in the relative abundance of this protein and the alpha (or fast) heavy subunit of cardiac myosin correlate with the contractile velocity of cardiac muscle. Its expression is also altered during thyroid hormone depletion and hemodynamic overloading. Mutations in this gene are associated with familial hypertrophic cardiomyopathy, myosin storage myopathy, dilated cardiomyopathy, and Laing distal myopathy. [provided by RefSeq, May 2022]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a helix (size 120) in uniprot entity MYH7_HUMAN there are 91 pathogenic changes around while only 3 benign (97%) in NM_000257.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr14-23424144-T-G is described in Lovd as [Likely_pathogenic].
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MYH7. . Gene score misZ 3.9329 (greater than the threshold 3.09). Trascript score misZ 6.7889 (greater than threshold 3.09). GenCC has associacion of gene with hyaline body myopathy, MYH7-related skeletal myopathy, dilated cardiomyopathy 1S, congenital myopathy 7A, myosin storage, autosomal dominant, dilated cardiomyopathy, left ventricular noncompaction, myopathy, myosin storage, autosomal dominant, hypertrophic cardiomyopathy, congenital heart disease, Ebstein anomaly, arrhythmogenic right ventricular cardiomyopathy, myopathy, myosin storage, autosomal recessive, hypertrophic cardiomyopathy 1, familial isolated dilated cardiomyopathy.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH7	NM_000257.4	c.2683C>A	p.Gln895Lys	missense_variant	23/40	ENST00000355349.4	NP_000248.2
MYH7	NM_001407004.1	c.2683C>A	p.Gln895Lys	missense_variant	22/39		NP_001393933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4	c.2683C>A	p.Gln895Lys	missense_variant	23/40	1	NM_000257.4	ENSP00000347507.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461824 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 727212

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: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jan 05, 2017

This missense change is denoted p.Glu895Lys (E895K) at the protein level and c.2683 C>A at the cDNA level. The Gln895Lys variant in the MYH7 gene has not been reported previously as a disease-causing mutation nor as a benign polymorphism, to our knowledge. Gln895Lys results in a semi-conservative amino acid substitution of a neutral, polar Glutamine with a positively charged Lysine at a residue that is conserved across species. Mutations in nearby codons (Glu894Gly, Ala901Gly, Ala901Pro) have been reported in association with HCM, supporting the functional importance of this region of the protein. The NHLBI ESP Exome Variant Server reports Gln895Lys was not observed in approximately 5,000 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. In summary, while the Gln895Lys variant is a good candidate for a disease-causing mutation, we cannot unequivocally determine whether Gln895Lys is a pathogenic mutation or a benign variant. The variant is found in HCM panel(s). -

Hypertrophic cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 19, 2021

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. This variant is found within a region of MYH7 between codons 181 and 937 that contains the majority of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C45"). This variant has been observed in individuals affected with hypertrophic cardiomyopathy (PMID: 27532257, Invitae). ClinVar contains an entry for this variant (Variation ID: 181376). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamine with lysine at codon 895 of the MYH7 protein (p.Gln895Lys). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and lysine. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 04, 2024

The p.Q895K variant (also known as c.2683C>A), located in coding exon 21 of the MYH7 gene, results from a C to A substitution at nucleotide position 2683. The glutamine at codon 895 is replaced by lysine, an amino acid with similar properties. This alteration is located in the myosin head domain, which contains a statistically significant clustering of pathogenic missense variants (Homburger JR et al. Proc Natl Acad Sci U S A, 2016 06;113:6701-6; Walsh R et al. Genet Med, 2017 02;19:192-203; Ambry internal data). This alteration has been reported in a hypertrophic cardiomyopathy (HCM) cohort (Walsh R et al. Genet Med, 2017 Feb;19:192-203). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
CardioboostCm	Uncertain	0.17
BayesDel_addAF	Uncertain	0.091	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.70	D
Eigen	Benign	0.19
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.78	D
MetaRNN	Uncertain	0.74	D
MetaSVM	Uncertain	0.27	D
MutationAssessor	Benign	1.6	L
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.40
Sift	Benign	0.13	T
Sift4G	Benign	0.76	T
Polyphen		0.61	P
Vest4		0.55
MutPred		0.54		Gain of ubiquitination at Q895 (P = 0.006);
MVP		0.98
MPC		1.4
ClinPred		0.36	T
GERP RS		5.5
Varity_R		0.50
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs397516162; hg19: chr14-23893355;