14-23430583-C-G

Position:

chr14-23430583-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PP2PP3_Strong

The NM_000257.4(MYH7):c.976G>C(p.Ala326Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000107 in 1,613,828 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A326T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

MYH7
NM_000257.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:13

Conservation

PhyloP100: -0.488

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 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, 11 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, 0.953

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH7	NM_000257.4 linkuse as main transcript	c.976G>C	p.Ala326Pro	missense_variant	11/40	ENST00000355349.4
MYH7	NM_001407004.1 linkuse as main transcript	c.976G>C	p.Ala326Pro	missense_variant	10/39

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH7	ENST00000355349.4 linkuse as main transcript	c.976G>C	p.Ala326Pro	missense_variant	11/40	1	NM_000257.4	P1

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000876

AC:

AN:

251204

Hom.:

AF XY:

0.0000884

AC XY:

AN XY:

135766

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000167

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000112

AC:

164

AN:

1461664

Hom.:

Cov.:

AF XY:

0.000128

AC XY:

AN XY:

727128

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0000447

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:

0.000143

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152164

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000450

Hom.:

Bravo

AF:

0.0000604

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000659

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 05, 2019	The p.Ala326Pro variant has been reported in 3 individuals with HCM (Michels 2009, D'Argenio 2014, LMM data). It has been identified in 19/126594 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs372731424). Clinvar: VUS (GeneDx, Invitae, CSER). Furthermore, alanine (Ala) at position 326 is not conserved in mammals or evolutionarily distant species, and the change to proline (Pro) was predicted to be benign using a computational tool clinically validated by our laboratory. This tool's benign prediction is estimated to be correct 89% of the time (Jordan 2011). In summary, due to conflicting data, the clinical significance of the p.Ala326Pro variant is uncertain. -
Uncertain significance, criteria provided, single submitter	clinical testing	Blueprint Genetics	Feb 27, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 23, 2023	Has been reported in association with HCM in individuals tested at GeneDx, and in published literature; however, some individuals harbored additional cardiogenetic variants (PMID: 27532257, 24183960, 27247418, 27153395, 19666645, 30696458, 27476098, 29300372, 35653365); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27153395, 29447731, 24183960, 25637381, 27247418, 19666645, 23299917, 31513939, 34426522, 27532257, 30696458, 34111116, 27476098, 32627857, 31323898, 32369506, 34542152, 29300372, 35653365) -

Cardiomyopathy

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Dec 08, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 20, 2023	This missense variant replaces alanine with proline at codon 326 of the MYH7 protein. Computational prediction is inconclusive regarding the impact of this variant 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 hypertrophic cardiomyopathy (PMID: 19666645, 24183960, 27247418, 27476098, 27532257, 30696458, 31323898, 32369506, 33495597, 37466024) and in an individual affected with noncompaction cardiomyopathy (PMID: 29447731). A family member of one proband was a healthy carrier (PMID: 24183960). This variant has also been identified in 25/282608 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

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 07, 2022	This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 326 of the MYH7 protein (p.Ala326Pro). This variant is present in population databases (rs372731424, gnomAD 0.02%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 19666645, 24183960, 27247418, 27532257, 31513939). ClinVar contains an entry for this variant (Variation ID: 43117). 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. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Human Genetics, University of Leuven	Oct 31, 2018	- -

Hypertrophic cardiomyopathy 1

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Dec 01, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Myosin storage myopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Sep 06, 2017

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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Congenital myopathy with fiber type disproportion;C1834481:Dilated cardiomyopathy 1S;C1842160:Myosin storage myopathy;C1850709:Myopathy, myosin storage, autosomal recessive;C3495498:Hypertrophic cardiomyopathy 1;C4552004:MYH7-related skeletal myopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Primary familial hypertrophic cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

Low GERP score may suggest that this variant may belong in a lower pathogenicity class -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 06, 2021

The c.976G>C (p.A326P) alteration is located in exon 11 (coding exon 9) of the MYH7 gene. This alteration results from a G to C substitution at nucleotide position 976, causing the alanine (A) at amino acid position 326 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.65

CardioboostCm

Uncertain

0.49

BayesDel_addAF

Benign

-0.034

BayesDel_noAF

Uncertain

-0.030

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.80

Eigen

Benign

-0.72

Eigen_PC

Benign

-0.89

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.77

M_CAP

Pathogenic

0.94

MetaRNN

Pathogenic

0.95

MetaSVM

Uncertain

0.51

MutationAssessor

Uncertain

2.4

MutationTaster

Benign

0.85

PrimateAI

Benign

0.34

PROVEAN

Benign

-1.8

REVEL

Pathogenic

0.66

Sift

Uncertain

0.019

Sift4G

Benign

0.25

Polyphen

0.11

Vest4

0.81

MVP

0.83

MPC

2.2

ClinPred

0.10

GERP RS

-3.0

Varity_R

0.72

gMVP

0.89

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

Other links and lift over