rs397516238

chr14-23432502-T-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Moderate

The NM_000257.4(MYH7):c.507A>T(p.Arg169Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R169G) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYH7 NM_000257.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -1.71

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 Pathogenic. Variant got 11 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain 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 chr14-23432504-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 177664.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP2: Missense variant where missense usually causes diseases, MYH7
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.901
• PP5: Variant 14-23432502-T-A is Pathogenic according to our data. Variant chr14-23432502-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 43055.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-23432502-T-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH7	NM_000257.4	c.507A>T	p.Arg169Ser	missense_variant	6/40	ENST00000355349.4
MYH7	NM_001407004.1	c.507A>T	p.Arg169Ser	missense_variant	5/39

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH7	ENST00000355349.4	c.507A>T	p.Arg169Ser	missense_variant	6/40	1	NM_000257.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypertrophic cardiomyopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 15, 2017

p.Arg169Ser, c.507A>T (MYH7; NM_000257.2; Chr14g.23901711T>A; GRCh37): The p.Arg 169Ser variant in MYH7 has not been previously reported in individuals with HCM and was absent from large population studies. Arginine (Arg) at position 169 is highly conserved in mammals and across evolutionarily distant species and the ch ange to Serine (Ser) was predicted to be pathogenic using a computational tool c linically validated by our laboratory. This tool's pathogenic prediction is esti mated to be correct 94% of the time (Jordan 2011). Of note, this variant lies in the head region of the protein. Missense variants in this region have been repo rted and statistically indicated to be more likely to cause disease (Walsh 2016) . In addition, two other amino acid substitutions involving this codon, p.Arg169 Gly and p.Arg169Lys, have also been identified in affected individuals (Maron 20 09, LMM data). In summary, although additional studies are required to fully est ablish its clinical significance, the p.Arg169Ser variant is likely pathogenic. ACMG/AMP Criteria applied: PM1, PM2, PM5, PP3. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
CardioboostCm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.30
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D
Eigen	Benign	0.037
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.078	N
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Uncertain	0.63	D
MutationAssessor	Benign	1.9	L
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-4.5	D
REVEL	Pathogenic	0.68
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.017	D
Polyphen		1.0	D
Vest4		0.90
MutPred		0.53		Gain of disorder (P = 0.0541);
MVP		0.89
MPC		2.2
ClinPred		0.95	D
GERP RS		-0.49
Varity_R		0.86
gMVP		0.94

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: rs397516238; hg19: chr14-23901711;