rs372731424

Positions:

• chr14-23430583-C-G
• chr14-23430583-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PP2 PP3_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
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:13
• Conservation: PhyloP100: -0.488

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_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 where missense usually causes diseases, MYH7
• 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	c.976G>C	p.Ala326Pro	missense_variant	11/40	ENST00000355349.4
MYH7	NM_001407004.1	c.976G>C	p.Ala326Pro	missense_variant	10/39

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152164 Hom.: 0 Cov.: 32

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: 22 AN: 251204 Hom.: 0 AF XY: 0.0000884 AC XY: 12 AN XY: 135766

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.: 0 Cov.: 32 AF XY: 0.000128 AC XY: 93 AN XY: 727128

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: 9 AN: 152164 Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6 AN XY: 74352

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.: 0

Bravo AF: 0.0000604

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000659 AC: 8

EpiCase AF: 0.000109

EpiControl AF: 0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Blueprint Genetics	Feb 27, 2019	- -
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	GeneDx	Dec 03, 2018	The A326P variant of uncertain significance in the MYH7 gene has been reported in association with HCM (Michels et al., 2009; D'Argenio et al, 2014; Homburger et al., 2016; Walsh et al., 2017). Michels et al. (2009) identified A326P in two unrelated probands with HCM as well as in two asymptomatic relatives, who had mild evidence of HCM upon clinical evaluation. A326P was also identified in an individual diagnosed with HCM shortly after birth, who harbored additional variants in the MYH7 and INS-IGF2 genes (D'Argenio et al, 2014). The A326P variant was inherited from the proband's clinically unaffected father (D'Argenio et al, 2014). This variant has also been identified, both independently and in conjunction with additional cardiogenetic variants, in other unrelated individuals referred for cardiomyopathy genetic testing at GeneDx; segregation data are limited or absent due to the lack of clinical information provided and/or insufficient participation by informative family members.The A326P variant is observed in 19/126,594 (0.015%) alleles from individuals of European (non-Finnish) ancestry in large population cohorts (Lek et al., 2016). A326P is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In addition, this variant is located in the myosin motor domain, a region enriched with missense variants reported in association with HCM (Walsh et al., 2017; Kelly et al., 2018). However, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign. -

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

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	T
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	10
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.80	D
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.77	T
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	0.51	D
MutationAssessor	Uncertain	2.4	M
MutationTaster	Benign	0.85	D
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.8	N
REVEL	Pathogenic	0.66
Sift	Uncertain	0.019	D
Sift4G	Benign	0.25	T
Polyphen		0.11	B
Vest4		0.81
MVP		0.83
MPC		2.2
ClinPred		0.10	T
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

Other links and lift over

dbSNP: rs372731424; hg19: chr14-23899792;