chr14-23431781-T-G

Position:

chr14-23431781-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PP2PP3_ModeratePP5

The NM_000257.4(MYH7):c.619A>C(p.Lys207Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 1,614,128 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). Synonymous variant affecting the same amino acid position (i.e. K207K) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

MYH7
NM_000257.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6U:3

Conservation

PhyloP100: 3.12

Variant links:

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]

MYH7 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in NM_000257.4

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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.91

PP5

Variant 14-23431781-T-G is Pathogenic according to our data. Variant chr14-23431781-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 177674.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=6, Uncertain_significance=2}. Variant chr14-23431781-T-G is described in Lovd as [Pathogenic]. Variant chr14-23431781-T-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH7	NM_000257.4 linkuse as main transcript	c.619A>C	p.Lys207Gln	missense_variant	7/40	ENST00000355349.4
MYH7	NM_001407004.1 linkuse as main transcript	c.619A>C	p.Lys207Gln	missense_variant	6/39

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH7	ENST00000355349.4 linkuse as main transcript	c.619A>C	p.Lys207Gln	missense_variant	7/40	1	NM_000257.4	P1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000144

AC:

AN:

1461892

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

727248

show subpopulations

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:

0.0000189

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152236

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74372

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6Uncertain:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hypertrophic cardiomyopathy

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	May 22, 2023	The c.619A>C (p.Lys207Gln) variant in the MYH7 gene has been identified in at least five individuals with Hypertrophic Cardiomyopathy (HCM) (PMID: 24793961, 27247418, 27532257, 25611685, 32894683). This variant has also been reported in homozygous status in a patient diagnosed at 47 years old with HCM that later seemed to transition to dilated cardiomyopathy at 64 years old. His sibling (80 years old) who is heterozygous for this variant was also diagnosed with HCM, while his three children (age range 40-46 years old) and three grandchildren (age range 3-15 years old) who were heterozygous for this variant were asymptomatic. Five of these heterozygous individuals have a resting sinus bradycardia, suggesting an alternative phenotypic expression (PMID: 12820698, 15528230). This variant is located in the established functional domain (amino acids 181-937) of the MYH7 protein without benign variations, and missense variants in this region are statistically more likely to be disease-associated (PMID:27532257). In-silico computational prediction tools suggest that this variant may have deleterious effect on the protein function (REVEL score: 0.801). This variant is found to be absent in the general population database (gnomAD) and interpreted as likely pathogenic by several submitters in the ClinVar database (ClinVar ID: 177674). Therefore, the c.619A>C (p.Lys207Gln) variant in the MYH7 gene is classified as likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 18, 2023	This sequence change replaces lysine, which is basic and polar, with glutamine, which is neutral and polar, at codon 207 of the MYH7 protein (p.Lys207Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in the heterozygous and homozygous state in individuals with hypertrophic cardiomyopathy (PMID: 12820698, 15528230, 27247418, 27532257, 32894683; Invitae). ClinVar contains an entry for this variant (Variation ID: 177674). 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. 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 25, 2020	proposed classification - variant undergoing re-assessment, contact laboratory -

Cardiomyopathy

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jul 28, 2020	This missense variant replaces lysine with glutamine at codon 207 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 individuals affected with hypertrophic cardiomyopathy (PMID: 12820698, 15528230, 24793961, 27247418, 27532257), including one individual in homozygous state with the disease onset at 47 years old. This variant is found within a highly conserved region of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Mar 10, 2021	- -

Primary familial hypertrophic cardiomyopathy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Oct 22, 2018

Variant summary: MYH7 c.619A>C (p.Lys207Gln) results in a conservative amino acid change located in the Myosin head, motor domain (IPR001609) and is found in a surface loop that spans the entrance to the ATP-binding pocket (Alpert 2005). Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 246666 control chromosomes (gnomAD and publication data). c.619A>C has been reported in the literature in a family with a homozygous individual affected with Hypertrophic Cardiomyopathy (HCM) that later seemed to transition into Dilated Cardiomyopathy (DCM); although the variant was found in several family members in heterozygosity, only one of them was affected by HCM (Mohiddin 2003, Alpert 2005). The variant was also reported to be found in HCM patient cohorts in heterozygous state (Bos 2014, Homburger 2016, Walsh 2017). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, characterizing skeletal muscle myosin from biceps muscles of the homozygous patient, however, this study does not allow convincing conclusions about the variant effect (Alpert 2005). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic, and the other laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

not specified

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Jul 24, 2014

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.Lys207Gln (c.619 A>C) in MYH7 (NM_000257.2) We have seen this in a patient with early onset HCM, severe LVH, who also carries p.Ile736Val (c.2206 A>G) in MYH7 (NM_000257.2) (phase not known). As reviewed below, we classify both of these variants as variants of uncertain significance, probably disease causing. They are good candidates, either individually or in combination, for the cause of his cardiomyopathy, however we cannot currently conclude with sufficient confidence that they are in fact the causative variants. The variant has been seen in at least two unrelated cases of HCM (not including this patient's family). Mohiddin et al (2003) reported a patient with HCM who was homozygous for this variant. The patient was from an NIH cohort of 100 HCM patients who had analysis of just MYH7. HCM was diagnosed at 47 years of age and at 64yo the maximal wall thickness was 2.1 cm, at the apex. History included syncope, appropriate shocks from his ICD, chronic atrial fibrillation, eventual left ventricular dilatation and heart failure class III symptoms. A sibling was a heterozygote and got diagnosed with HCM at 80yo with a thickness of 3.5 cm. Three children in their 40s were heterozygotes and had normal echos. Three grandchildren <16 yo Were also heterozygotes and had normal echos. Several heterozygotes had resting sinus bradycardia. Ancestry was not reported. Consanguinity was denied and haplotype analysis was not reported. The same case was included in a later publication by this group (Alpert et al 2005). Dr. Ackerman's group reported 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. We have not seen this variant before. It is not currently listed in ClinVar (as of July 3rd, 2014). In silico analysis with PolyPhen-2 predicts the variant to be possibly damaging (HumVar score 0.551). The lysine at codon 207 is conserved across all mammalian cardiac myosins, regardless of isoform (Alper et al 2002). Other variants have been reported in association with disease at nearby codons (Ala199Val, Ala200Thr, Ile201Thr, Arg204His, Ser205Cys, Q209E, Pro211Leu, Gly214Asp, Leu216Val per GeneDx report, referencing HGMD). In total the variant has not been seen in 6800 published controls and individuals from publicly available population datasets. There is no variation at codon 207 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6500 Caucasian and African American individuals (as of July 3rd, 2014). There is also no variation at this codon listed in dbSNP (as of July 3rd, 2014). The variant was not observed in the following published control samples: 100 (Mohiddin et al 2003), 200 (Bos et al 2014). -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 13, 2022

The variant has been reported in association with HCM in one large family with a proband homozygous for the variant. The variant segregated with HCM in one family member (PMID: 12820698;15528230); Identified in the heterozygous state in other unrelated individuals with diagnosis of HCM in the published literature (PMID: 27532257; 27247418) and independently and/or in conjunction with additional cardiogenetic variants in individuals referred for cardiomyopathy at GeneDx, but segregation data is limited or absent at this time.; Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 18391120, 21310275, 27247418, 28420666, 20298698, 12820698, 15528230, 27532257, 29300372, 32894683, 18761664) -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 11, 2023

The p.K207Q variant (also known as c.619A>C), located in coding exon 5 of the MYH7 gene, results from an A to C substitution at nucleotide position 619. The lysine at codon 207 is replaced by glutamine, an amino acid with similar properties. This alteration was reported in the homozygous state in an individual with apical hypertrophic cardiomyopathy (HCM), and in the heterozygous state in multiple family members, only one of whom also had HCM (Mohiddin SA et al. Genet. Test., 2003;7:21-7; Alpert NR et al. Am. J. Physiol. Heart Circ. Physiol., 2005 Mar;288:H1097-102). This alteration has also been reported in other HCM cohorts, though clinical details were limited (Homburger JR et al. Proc. Natl. Acad. Sci. U.S.A., 2016 06;113:6701-6; Walsh R et al. Genet. Med., 2017 Feb;19:192-203). 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 amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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

0.24

CardioboostCm

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.25

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.70

Eigen

Benign

0.12

Eigen_PC

Benign

0.084

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.81

M_CAP

Pathogenic

0.83

MetaRNN

Pathogenic

0.91

MetaSVM

Uncertain

0.67

MutationAssessor

Benign

0.94

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-1.6

REVEL

Pathogenic

0.80

Sift

Uncertain

0.023

Sift4G

Benign

0.082

Polyphen

0.75

Vest4

0.72

MutPred

0.71

Loss of ubiquitination at K207 (P = 0.0039);

MVP

0.96

MPC

2.2

ClinPred

0.82

GERP RS

3.1

Varity_R

0.44

gMVP

0.86

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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