rs376897125

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_000257.4(MYH7):​c.958G>A​(p.Val320Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,613,992 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V320E) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

MYH7
NM_000257.4 missense

Scores

13
6
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12U:1

Conservation

PhyloP100: 7.77
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 17 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr14-23430600-A-T is described in Lovd as [Likely_pathogenic].
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, 0.963
PP5
Variant 14-23430601-C-T is Pathogenic according to our data. Variant chr14-23430601-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 161328.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23430601-C-T is described in Lovd as [Pathogenic]. Variant chr14-23430601-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MYH7NM_000257.4 linkuse as main transcriptc.958G>A p.Val320Met missense_variant 11/40 ENST00000355349.4 NP_000248.2 P12883
MYH7NM_001407004.1 linkuse as main transcriptc.958G>A p.Val320Met missense_variant 10/39 NP_001393933.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MYH7ENST00000355349.4 linkuse as main transcriptc.958G>A p.Val320Met missense_variant 11/401 NM_000257.4 ENSP00000347507.3 P12883

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152178
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
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:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000159
AC:
4
AN:
251342
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135820
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.00
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:
0.0000264
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461814
Hom.:
0
Cov.:
32
AF XY:
0.00000138
AC XY:
1
AN XY:
727202
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:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152178
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74350
show subpopulations
Gnomad4 AFR
AF:
0.0000241
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:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000167
Hom.:
0
Bravo
AF:
0.0000529
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000233
AC:
2
ExAC
AF:
0.00000824
AC:
1
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:12Uncertain:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:3
Likely pathogenic, criteria provided, single submitterclinical testingRevvity Omics, RevvityJan 17, 2022- -
Likely pathogenic, criteria provided, single submitterclinical testingGeneDxJun 30, 2024Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23299917, 24093860, 25637381, 23197161, 22429680, 12566107, 27247418, 27532257, 22857948, 21239446, 33588347, 20031602, 33673806, 34542152, 25937619, 33764162, 29300372, 37652022, 28771489) -
Likely pathogenic, no assertion criteria providedclinical testingStanford Center for Inherited Cardiovascular Disease, Stanford UniversityAug 06, 2012Note 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.Val320Met (c.958 G>A) in the MYH7 gene. We re-reviewed these results on 6/27/2012 and again on 10/1/13 and February 9th, 2015. Based on the strong case data and very low frequency in the general population, we consider this variant likely disease causing. The variant has been seen in at least 10 unrelated cases of HCM (not including this patient). There is weak segregation data. Havndrup et al (2003) observed this variant in a Danish woman with HCM (likely the same case that was included in Ho et al 2009). Her 15yo daughter had a proximal 'septal bulb' and also carried the variant. Fokstuen et al (2011) observed the variant in one patient with HCM recruited from Europe (not Denmark). Santos et al (2012) reported the variant in one patient with HCM in their Portugese cohort. We have seen this variant in one other HCM patient in our cohort. She had 12 HCM genes sequenced at PGxHealth/Familion and only this variant was found. Marsiglia et al (2013) sequenced MYH7, MYBPC3, TNNT2 in 268 Brazilian patients with HCM and found the variant in 5 patients. Alvarez-Acosta et al (2014) reported the variant in 1 of 124 HCM patients recruited from a clinic in Spain. It isn't entirely clear but it looks like the patient underwent sequencing of MYH7, MYBPC3, TNNT2, TNNI3, TPM1, ACTC, MYL2, MYL3, TNNC1. The patient also had a variant in MYL2. He had a relatively severe phenotyped, diagnosed at 16yo, with atrial fibrillation, 2.6 cm wall thickness, syncope, left ventricular outflow tract obstruction, heart failure, LBBB, ICD, and underwent alcohol ablation. His first cousin carried only the MYL2 variant and also had HCM. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging. The valine at codon 320 is completely conserved across species, though not all neighboring amino acids are. I could not find any other variants reported in association with disease at this codon, though there are a few at nearby codons (p.Phe312Cys, p.Ala326Pro). In total the variant has been seen in ~1-4/60,452 published controls, laboratory controls, and publicly available population datasets. The variant was reported online in 2 of 4300 Caucasian individuals and 0 of 2203 African-American individuals in the NHLBI Exome Sequencing Project dataset (as of 10/1/13). The phenotype of those individuals is not publicly available, however the cohorts that were merged to create this dataset were all either general population samples or samples recruited for common cardiovascular disease such as hypertension. Of note, variants with strong evidence for pathogenicity have been observed at similar low frequencies in this data set. The variant was reported online in 1 of 59,906 individuals 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 February 9th, 2015). Specifically, the variant was observed in 1 individual of African descent. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Of note, the ESP and ExAC databases overlap (ExAC includes ESP). The discrepancy between them may be attributable to the primary data being re-analyzed in ExAC. The Seidman group observed the variant in 2 of 1963 individuals from the Jackson Heart Study who underwent sequencing of eight sarcomere genes (Bick et al 2012). They note the following about those individuals phenotypes: a 41yo with left ventricular wall thickness of 1 cm, LVDD of 4.2, LAD of 3.83, and FS of 0.38 and no known physiological risk factors; a 63yo -
Hypertrophic cardiomyopathy Pathogenic:3
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 19, 2023This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 320 of the MYH7 protein (p.Val320Met). This variant is present in population databases (rs376897125, gnomAD 0.007%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 12566107, 20031602, 21239446, 22857948, 24093860, 27247418). ClinVar contains an entry for this variant (Variation ID: 161328). 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%. 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). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitterclinical testingAll of Us Research Program, National Institutes of HealthJul 29, 2024This missense variant replaces valine with methionine at codon 320 of the MYH7 protein. 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). 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 at least thirteen unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 12566107, 21239446, 22857948, 24093860, 27532257, 28771489, 30775854, 33588347, 33764162). This variant has been identified in 4/251342 chromosomes 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 submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineFeb 06, 2023The p.Val320Met variant in MYH7 has been reported in over 20 individuals with hypertrophic cardiomyopathy (HCM; Brito 2012 PMID: 22857948, Fokstuen 2011 PMID: 21239446, Havndrup 2003 PMID: 12566107, Homburger 2016 PMID: 27247418, Jensen 2013 PMID: 23197161, Marsiglia 2013 PMID: 24093860, Walsh 2017 PMID: 27532257, LMM data) and segregated with disease in at least one affected relative from one family (Havndrup 2003 PMID: 12566107). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID: 161328) and has also been identified in 0.0029% (2/68040) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.1). Computational prediction tools and conservation analysis are consistent with pathogenicity. This variant lies in the head region of the protein and missense variants in this region are statistically more likely to be disease-associated (Walsh 2017 PMID: 27532257). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant HCM. ACMG/AMP criteria applied: PS4, PM2_Supporting, PP3, PM1. -
Hypertrophic cardiomyopathy 1 Pathogenic:3
Likely pathogenic, criteria provided, single submitterclinical testingLaboratory of Genetics and Molecular Cardiology, University of São Paulo-- -
Likely pathogenic, criteria provided, single submitterclinical testingVictorian Clinical Genetics Services, Murdoch Childrens Research InstituteJun 11, 2020Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Likely Pathogenic. ClinGen MYH7 guidelines: Likely Pathogenic: PM1 + PM2 + PS4 + PP3 Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established; however, missense variants have been proposed to act in a dominant negative manner (PMID: 24714796) (N) 0108 - This gene is known to be associated with both recessive and dominant disease (OMIM) (N) For this patient: autosomal dominant inheritance with digenic dominance applies (Cardiomyopathy, hypertrophic, 1. OMIM: 192600) 0112 - Variants in this gene are known to have reduced penetrance: PMID: 29300372: Kelly, MA. et al. (2018), Florescu, C. (2017) (N) 0200 - Variant is predicted to result in a missense amino acid change from valine to methionine (exon 11). (N) 0251 - Variant is heterozygous. (N) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (0.0000159 (4 Het, 0 Hom) gnomAD v2.1.1. (P) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (P) 4/4 in silico analyses. Minor amino acid. High conservation. 0602 - Variant is located in a hotspot region or cluster of pathogenic variants. (P) Hotspot region (amino acids 181-937) (PMID: 29300372). 0708 Comparable variants have conflicting previous evidence for pathogenicity. (N) p.(Val320Glu), major amino acid change: Likely pathogenic in ClinVar x1. LOVD3: 2x Likely pathogenic + 2x VUS by VKGL data sharing initiative. 0801 Strong previous evidence of pathogenicity in unrelated individuals. (P) >15 unrelated probands with this variant. ClinVar: Conflicting interpretations of pathogenicity: 7 submissions: 5x Likely Pathogenic + 2x VUS. Publications: PMID: 12566107 (and follow-up PMID: 23197161). PMID: 21239446. PMID: 22857948. PMID: 24093860. Álvarez-Acosta, L. et al. (2014). PMID: 27247418. PMID: 27532257. 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -
Likely pathogenic, criteria provided, single submitterresearchHudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for BiotechnologyMar 10, 2020- -
Primary familial hypertrophic cardiomyopathy Pathogenic:1Uncertain:1
Likely pathogenic, no assertion criteria providedclinical testingBlueprint GeneticsJun 09, 2014- -
Uncertain significance, no assertion criteria providedresearchCSER _CC_NCGL, University of WashingtonJun 01, 2014- -
Cardiomyopathy Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthApr 19, 2022This missense variant replaces valine with methionine at codon 320 of the MYH7 protein. 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). 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 at least thirteen unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 12566107, 21239446, 22857948, 24093860, 27532257, 28771489, 30775854, 33588347, 33764162). This variant has been identified in 4/251342 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Cardiovascular phenotype Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsNov 28, 2023The c.958G>A (p.V320M) alteration is located in exon 11 (coding exon 9) of the MYH7 gene. This alteration results from a G to A substitution at nucleotide position 958, causing the valine (V) at amino acid position 320 to be replaced by a methionine (M). Based on data from gnomAD, the A allele has an overall frequency of 0.002% (4/251342) total alleles studied. The highest observed frequency was 0.006% (1/16250) of African alleles. This variant has been reported in numerous hypertrophic cardiomyopathy cohorts (Havndrup, 2003; Brito, 2012; Jensen, 2013; Marsiglia, 2013). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is located in the myosin head domain, which contains a statistically significant clustering of pathogenic missense variants (Homburger, 2016; Walsh, 2017; Ambry internal data). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.96
CardioboostCm
Pathogenic
0.98
BayesDel_addAF
Pathogenic
0.30
D
BayesDel_noAF
Pathogenic
0.38
CADD
Pathogenic
31
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.94
D
Eigen
Uncertain
0.66
Eigen_PC
Uncertain
0.46
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.95
D
M_CAP
Pathogenic
0.95
D
MetaRNN
Pathogenic
0.96
D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Pathogenic
3.4
M
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.76
T
PROVEAN
Uncertain
-2.6
D
REVEL
Pathogenic
0.90
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0010
D
Polyphen
1.0
D
Vest4
0.94
MVP
0.93
MPC
2.1
ClinPred
0.96
D
GERP RS
3.4
Varity_R
0.79
gMVP
0.65

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.

Other links and lift over

dbSNP: rs376897125; hg19: chr14-23899810; COSMIC: COSV62517894; API