rs397516167

Positions:

• chr14-23424110-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP2

The NM_000257.4(MYH7):​c.2719C>A​(p.Gln907Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. Q907P) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYH7 NM_000257.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.08

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 Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_000257.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, MYH7

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH7	NM_000257.4	c.2719C>A	p.Gln907Lys	missense_variant	23/40	ENST00000355349.4
MYH7	NM_001407004.1	c.2719C>A	p.Gln907Lys	missense_variant	22/39

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH7	ENST00000355349.4	c.2719C>A	p.Gln907Lys	missense_variant	23/40	1	NM_000257.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 27, 2011

The Gln907Lys variant has not been reported in the literature but has been detec ted in 2/90 Hispanic cardiomyopathy probands tested by our laboratory. Because h ealthy control information is unavailable for this population we are unable to e xclude that this variant is common and therefore benign. In one of the families, the variant was present in 3 affected individuals, whcih is consistent with a p athogenic role. However, glutamine (Gln) at amino acid position 907 is conserved in mammals and chicken but not in evolutionary distant species (zebrafish fish carries a glycine), reducing the likelihood that the change is pathogenic. In ad dition, computational predictions are inconsistent. Three tools (AlignGVGD, SIF T, MAPP) predict that the variant is deleterious but their accuracy is unknown. In contrast, the variant was predicted to be benign using a novel tool, which wa s validated by our laboratory using a set of cardiomyopathy variants with well-e stablished clinical significance. This tool's benign prediction is estimated to be correct 89% of the time (Jordan 2011). In summary, additional data (healthy c ontrol studies and familial segregation) are needed to determine the clinical si gnificance of this variant. -

Hypertrophic cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 09, 2024

This sequence change replaces glutamine, which is neutral and polar, with lysine, which is basic and polar, at codon 907 of the MYH7 protein (p.Gln907Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 42928). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MYH7 protein function. 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). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
CardioboostCm	Benign	0.070
BayesDel_addAF	Uncertain	0.024	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.67	D
Eigen	Benign	0.10
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.72	D
MetaRNN	Uncertain	0.64	D
MetaSVM	Uncertain	-0.068	T
MutationAssessor	Benign	1.3	L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.40
Sift	Benign	0.16	T
Sift4G	Benign	0.82	T
Polyphen		0.51	P
Vest4		0.56
MutPred		0.51		Gain of ubiquitination at Q907 (P = 0.0198);
MVP		0.97
MPC		1.8
ClinPred		0.55	D
GERP RS		5.5
Varity_R		0.58
gMVP		0.91

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: rs397516167; hg19: chr14-23893319;