chr14-23423939-C-G

Position:

• chr14-23423939-C-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2 BS1

The ENST00000355349.4(MYH7):​c.2890G>C​(p.Val964Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000832 in 1,614,220 control chromosomes in the GnomAD database, including 1 homozygotes. 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. V964A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00049 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00087 (1 hom.)
• Consequence: MYH7 ENST00000355349.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:11 B:12
• Conservation: PhyloP100: 7.74

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_benign. Variant got -3 ACMG points.

• 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.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.000868 (1269/1461880) while in subpopulation NFE AF= 0.00107 (1190/1112010). AF 95% confidence interval is 0.00102. There are 1 homozygotes in gnomad4_exome. There are 611 alleles in male gnomad4_exome subpopulation. Median coverage is 34. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH7	NM_000257.4	c.2890G>C	p.Val964Leu	missense_variant	23/40	ENST00000355349.4	NP_000248.2
MYH7	NM_001407004.1	c.2890G>C	p.Val964Leu	missense_variant	22/39		NP_001393933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4	c.2890G>C	p.Val964Leu	missense_variant	23/40	1	NM_000257.4	ENSP00000347507	P1

Frequencies

GnomAD3 genomes AF: 0.000486 AC: 74 AN: 152222 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000970

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000433 AC: 109 AN: 251488 Hom.: 0 AF XY: 0.000412 AC XY: 56 AN XY: 135916

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000425

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000826

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000868 AC: 1269 AN: 1461880 Hom.: 1 Cov.: 34 AF XY: 0.000840 AC XY: 611 AN XY: 727238

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000441

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00107

Gnomad4 OTH exome AF: 0.000447

GnomAD4 genome AF: 0.000486 AC: 74 AN: 152340 Hom.: 0 Cov.: 32 AF XY: 0.000443 AC XY: 33 AN XY: 74498

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000970

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000759 Hom.: 0

Bravo AF: 0.000442

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000420 AC: 51

EpiCase AF: 0.00131

EpiControl AF: 0.000771

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:11 Benign:12

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:5 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 01, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 10, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 15, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 03, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	MYH7: PP2, PP3 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 03, 2021	This variant is associated with the following publications: (PMID: 23861362, 26220970, 23349452, 25163546, 23299917, 19412328, 22958901, 27247418, 25351510, 27153395, 27600940, 28771489, 24704860, 28807990, 28798025, 31737537, 30847666, 26582918, 27535533, 32880476) -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The MYH7 p.Val964Leu variant was identified in 3 of 1082 proband chromosomes (frequency: 0.0028) from individuals with dilated or hypertrophic cardiomyopathy (Maurizi_2018_PMID:29710196, Claes_2015_PMID:26497160, van-Spaendonck-Zwarts_2013_PMID:23349452). The variant was identified in dbSNP (ID: rs45496496) and ClinVar (classified as uncertain significance by GeneDx and nine other submitters, as likely benign by Invitae and two other submitters, and as likely pathogenic by Genomic Research Genter Shahid Beheshti University of Medical Sciences). The variant was identified in control databases in 124 of 282890 chromosomes at a frequency of 0.0004383 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 109 of 129196 chromosomes (freq: 0.000844), South Asian in 13 of 30616 chromosomes (freq: 0.000425) and Latino in 2 of 35440 chromosomes (freq: 0.000056), but was not observed in the African, Ashkenazi Jewish, East Asian, European (Finnish), or Other populations. The p.Val964 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Hypertrophic cardiomyopathy 1 Pathogenic:1 Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 09, 2023	Criteria applied: PP2, PP3 -
Likely pathogenic, no assertion criteria provided	clinical testing	Genomics England Pilot Project, Genomics England	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Dec 10, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	May 22, 2018	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not specified Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Uncertain significance, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Feb 25, 2015	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.Val964Leu (c.2890G>C) in the MYH7 gene. When the patient first had genetic testing, the variant was novel. Since then it has been seen in at least 12 additional cases of primary cardiomyopathy. The variant was reported in one individual with familial dilated cardiomyopathy and considered possibly pathogenic by the authors (Hershberger et al 2008). Gencor (a national registry with patients and families with a familial heart disease in the Netherlands) reported unpublished data on three patients in two families with the variant; however it is unclear which specific cardiac disease these individuals had (http://www.gencor.nl/gencor/docs/GencorNHJ2009november.pdf). I contacted them directly and they told me they have now seen this variant in four of 831 index HCM cases and an infant with LVNC. This is a conservative amino acid change with a nonpolar Valine replaced with a nonpolar Leucine. Valine is completely conserved at this position in the MYH7 gene, as are nearby residues. SIFT predicts the variant to be tolerated, while PolyPhen predicts it to be possibly damaging. A sarcomere-specific prediction tool that is estimated to be correct 94% of the time predicts the variant to be pathogenic (Jordan et al 2011). Additional variants associated with disease have been reported in nearby codons: p.Leu961Arg (Haluza et al 2001) and p.Asp953His (van Driest et al 2004). Hershberger et al (2008) did not find p.Val964Leu in 253 presumably healthy controls (188 Caucasian, 24 African American, 22 Asian and 19 Hispanic) Correlagen did not provide control data on this variant. GeneDx told me they did not observe the variant in 300 control individuals of various ethnicities. The variant is listed in dbSNP (rs45496496) with genotype frequency data from a general population sample from Coriell, noting the variant was absent in 231 individuals of various ethnicities. In addition, dbSNP notes that the variant was observed (ss342383782) in two of 2276 individuals studied through the NHLBI GO exome sequencing project (ESP), which consists of various large well-phenotyped cohorts (ex. WHI, Framingham, Jackson Heart Study, ARIC, CARDIA). No phenotypic information about the individuals who had this variant is provided. None of the cohorts listed were specific to HCM, though with their large sample sizes individuals with HCM likely would have been included due to chance alone. Thus, in total, the variant has been reported in 2 of 2960 general population individuals. -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 10, 2023	The p.Val964Leu variant in MYH7 is classified as likely benign because it has been identified in 0.1% (66/68046) of European chromosomes in gnomAD (http://gnomad.broadinstitute.org, v.3.1.2), at a frequency that is higher than expected for disease-causing variant in MYH7. ACMG/AMP Criteria applied: BS1 -

Cardiomyopathy Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 13, 2023	This missense variant replaces valine with leucine at codon 964 of the MYH7 protein. Computational prediction tool indicates that this variant may have an uncertain impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with dilated cardiomyopathy (PMID: 19412328, 23349452, 31568572, 35299955) and hypertrophic cardiomyopathy (PMID: 24704860). This variant has also been identified in 124/282890 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although the relatively high frequency of this variant in the general population suggests that this variant is unlikely to be disease-causing, 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	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Oct 12, 2021	- -

Hypertrophic cardiomyopathy Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Mar 01, 2024	- -

Primary dilated cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Apr 05, 2018

- -

Dilated cardiomyopathy 1S Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

May 22, 2018

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Myosin storage myopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

May 22, 2018

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

MYH7-related skeletal myopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

May 22, 2018

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Dilated Cardiomyopathy, Dominant Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 10, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
CardioboostCm	Benign	0.045
BayesDel_addAF	Benign	-0.080	T
BayesDel_noAF	Uncertain	0.090
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.71	D
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.87	D
M_CAP	Pathogenic	0.53	D
MetaRNN	Uncertain	0.61	D
MetaSVM	Uncertain	0.34	D
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.64
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.82	T
Polyphen		0.99	D
Vest4		0.73
MutPred		0.43		Gain of catalytic residue at L959 (P = 0.0843);
MVP		0.86
MPC		1.1
ClinPred		0.16	T
GERP RS		5.3
Varity_R		0.46
gMVP		1.0

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: rs45496496; hg19: chr14-23893148;