rs797045097

Positions:

• chr14-23418348-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PP2 PP3_Moderate PP5

The NM_000257.4(MYH7):​c.4031G>A​(p.Arg1344Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,613,748 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1344W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: MYH7 NM_000257.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:6
• Conservation: PhyloP100: 7.69

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 4 ACMG points.

• PP2: Missense variant where missense usually causes diseases, MYH7
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.933
• PP5: Variant 14-23418348-C-T is Pathogenic according to our data. Variant chr14-23418348-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 208597.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=6, Likely_pathogenic=2}. Variant chr14-23418348-C-T is described in Lovd as [Pathogenic]. Variant chr14-23418348-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH7	NM_000257.4	c.4031G>A	p.Arg1344Gln	missense_variant	30/40	ENST00000355349.4
MYH7	NM_001407004.1	c.4031G>A	p.Arg1344Gln	missense_variant	29/39

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH7	ENST00000355349.4	c.4031G>A	p.Arg1344Gln	missense_variant	30/40	1	NM_000257.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152220 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 250948 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135708

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000109 AC: 16 AN: 1461528 Hom.: 0 Cov.: 32 AF XY: 0.0000124 AC XY: 9 AN XY: 727046

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000809

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152220 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74374

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Oct 06, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	MYH7: PM1, PP3, PS4:Supporting -
Likely pathogenic, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Nov 03, 2011	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Arg1344Gln (c.4031G>A) in the MYH7 gene. Given the newly reported presence in cases around the world, the absence in unselected populations, we consider this variant likely disease causing. When the patient first had genetic testing the variant was novel, with no published data. Ackerman's group observed the variant in one patient in their cohort of 1053 unrelated patients with HCM who underwent DHLPC-based analysis of 9 sarcomere genes at Mayo (Bos et al 2014). Note that these cases may overlap with prior reports by Ackerman's group (ex. van Driest et al 2005). Arad et al (2014) reported the variant in a patient with HCM in their Israeli cohort. The patient presented at 13yo and had "massive LVH" (also described as "severe distal hypertrophy"), severe heart failure, and, reportedly, growth delay. It is unclear what genes were sequenced. Marsiglia et al (2013) observed the variant in one of 268 unrelated patients with HCM in their Brazilian cohort. Subjects underwent sequencing of MYH7, MYBPC3, TNNT2. There is no ClinVar entry (as of July 22nd, 2015) and there are no other cases in SHaRe. In silico analysis with Polyphen predicts this variant as probably damaging with a score of 0.984. MutationTaster predicts this variant to be disease causing with a score of 43. The Arganine at codon 1344 is completely conserved across species and isoforms. A polar positive Arginine is replaced with a polar neutral Glutamine. Another variant, p.Arg1344Trp has been reported with disease and is in ClinVar as pathogenic by GeneDx and a variant of uncertain significance by LMM. The variant is not listed in dbSNP or 1000 genomes (as of June 20, 2013). The variant is also not currently listed in the NHLBI Exome Sequencing Project dataset, which includes variant calls on ~6,500 Caucasian and African American individuals (as of June 20, 2013). Bos et al (2014) did not observe the variant in 200 "ostensibly healthy" individuals. This variant is not listed in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of July 22nd, 2015). However, another variant at that codon (p.Arg1344Trp) is present in 2 of 60,278 individuals. -

Cardiomyopathy Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 06, 2022	This missense variant replaces arginine with glutamine at codon 1344 of the MYH7 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in four unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 24093860, 24793961, 25558701, 29030401, 32894683), in an individual affected with left ventricular noncompaction (PMID: 34853230), and in an individual affected with sudden unexplained death (PMID: 31195250). This variant has been identified in 4/282350 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Oct 02, 2023	This missense variant replaces arginine with glutamine at codon 1344 of the MYH7 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in four unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 24093860, 24793961, 25558701, 29030401, 32894683), in an individual affected with left ventricular noncompaction (PMID: 34853230), and in an individual affected with sudden unexplained death (PMID: 31195250). This variant has been identified in 4/282350 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Hypertrophic cardiomyopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 19, 2024

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1344 of the MYH7 protein (p.Arg1344Gln). This variant is present in population databases (rs797045097, gnomAD 0.005%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 24093860, 24793961, 25558701, 27247418, 29030401, 32528171, 32894683). ClinVar contains an entry for this variant (Variation ID: 208597). 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 MYH7 protein function with a positive predictive value of 95%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Hypertrophic cardiomyopathy 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory of Genetics and Molecular Cardiology, University of São Paulo

-

- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 12, 2019

The p.Arg1344Gln variant in MYH7 has been reported in at least 3 individuals with HCM (Marsiglia 2013, Bos 2014, Cirino 2017, LMM data). It was also identified in 4/282350 chromosomes by gnomAD (https://gnomad.broadinstitute.org) and has been reported in ClinVar (Variation ID #208597). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2, PS4_Supporting, PP3. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 02, 2019

The p.R1344Q variant (also known as c.4031G>A), located in coding exon 28 of the MYH7 gene, results from a G to A substitution at nucleotide position 4031. The arginine at codon 1344 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in multiple individuals with hypertrophic cardiomyopathy (HCM) as well as once in a sudden unexplained death (SUD) cohort (Marsiglia JD et al. Am. Heart J., 2013 Oct;166:775-82; Bos JM et al. Mayo Clin. Proc., 2014 Jun;89:727-37; Arad M et al. Isr. Med. Assoc. J., 2014 Nov;16:707-13; Homburger JR et al. Proc. Natl. Acad. Sci. U.S.A., 2016 06;113:6701-6; Cirino AL et al. Circ Cardiovasc Genet, 2017 Oct;10:; Gando I et al. Forensic Sci. Int., 2019 Aug;301:289-298). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
CardioboostCm	Pathogenic	0.96
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.82	D
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Uncertain	0.50	D
MutationAssessor	Uncertain	2.6	M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-2.9	D
REVEL	Pathogenic	0.74
Sift	Uncertain	0.016	D
Sift4G	Benign	0.22	T
Polyphen		0.98	D
Vest4		0.95
MutPred		0.52		Gain of catalytic residue at L1342 (P = 0.0792);
MVP		0.97
MPC		1.7
ClinPred		0.95	D
GERP RS		5.0
Varity_R		0.40
gMVP		0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs797045097; hg19: chr14-23887557; COSMIC: COSV105912883; COSMIC: COSV105912883;