chr14-23431641-C-T

Variant names:

• chr14-23431641-C-T
• rs1057517773
• NM_000257.4:c.676G>A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5

The NM_000257.4(MYH7):​c.676G>A​(p.Ala226Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 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. A226V) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MYH7 NM_000257.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2
• Conservation: PhyloP100: 0.709
• Publications: 4 publications found

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 Gene-Disease associations (from GenCC):

• dilated cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• dilated cardiomyopathy 1S

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• hypertrophic cardiomyopathy 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• MYH7-related skeletal myopathy

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• myopathy, myosin storage, autosomal recessive

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• myopathy, myosin storage, autosomal dominant

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• congenital myopathy 7A, myosin storage, autosomal dominant

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Ebstein anomaly

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hyaline body myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• left ventricular noncompaction

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• congenital heart disease

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 20 uncertain in NM_000257.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr14-23431640-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 228918.
• PP2: Missense variant in the MYH7 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 341 curated pathogenic missense variants (we use a threshold of 10). The gene has 16 curated benign missense variants. Gene score misZ: 3.9329 (above the threshold of 3.09). Trascript score misZ: 6.7889 (above the threshold of 3.09). GenCC associations: The gene is linked to myopathy, myosin storage, autosomal recessive, MYH7-related skeletal myopathy, congenital myopathy 7A, myosin storage, autosomal dominant, Ebstein anomaly, hyaline body myopathy, left ventricular noncompaction, hypertrophic cardiomyopathy 1, dilated cardiomyopathy 1S, dilated cardiomyopathy, congenital heart disease, familial isolated dilated cardiomyopathy, myopathy, myosin storage, autosomal dominant, arrhythmogenic right ventricular cardiomyopathy, hypertrophic cardiomyopathy.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.924
• PP5: Variant 14-23431641-C-T is Pathogenic according to our data. Variant chr14-23431641-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 372429.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH7	NM_000257.4	c.676G>A	p.Ala226Thr	missense_variant	Exon 8 of 40	ENST00000355349.4	NP_000248.2
MYH7	NM_001407004.1	c.676G>A	p.Ala226Thr	missense_variant	Exon 7 of 39		NP_001393933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4	c.676G>A	p.Ala226Thr	missense_variant	Exon 8 of 40	1	NM_000257.4	ENSP00000347507.3
MYH7	ENST00000713768.1	c.676G>A	p.Ala226Thr	missense_variant	Exon 8 of 41			ENSP00000519070.1
MYH7	ENST00000713769.1	c.676G>A	p.Ala226Thr	missense_variant	Exon 7 of 39			ENSP00000519071.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Feb 27, 2017

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: provider interpretation

We have seen this variant in one case of HCM at our center. Testing was done at Invitae. Given it has only been published in one case, is rare, and the data on tolerance at this location is conflicted, we consider this variant a variant of uncertain significance, and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant has been seen in at least one unrelated case of HCM (not including this patient's family). There is no case data. Bottillo et al (2016) observed the variant in 1/44 patients with HCM in their cohort from Rome, Italy (authors are from “Sapienza University of Rome”). Cecconi et al (2016) and Rubattu et al (2016) also report a case of this variant. Given overlap in institution and at least one author for Bottillo et al and Rubattu et al, it seems reasonable to suspect they are reporting the same case (and the same cohort). It is more difficult to determine whether the Cecconi et al case is redundant. Unfortunately minimal to no case data is reported in these papers so it is difficult to assess whether the cases are distinct. The variant is not listed in ClinVar (as of 3 January 2016). The variant has not been observed in the SHaRe consortium and was not reviewed for the ClinGen MYH7 classification project. The variant was not reviewed for the ClinGen MYH7 pilot project. A different missense substitution at this codon (p.Ala226Val) has been reported with HCM and a different group has been determined to be pathogenic based on internal cases, in silico predictions, and absence in control populations. p.Ala226Val has been in seen in two patients with HCM in the SHaRe consortium, both cared for at the University of Michigan. One proband has an affected family member who also carries the variant. These individuals were tested at GeneDx and LMM so their case data overlaps with that of those two labs. These cases are also redundant with Homburger et al 2016 (PMID 27247418). Walsh et al (2016, PMID: 27532257) report p.Ala226Val was seen in 1 patient with HCM of 3200 patients with cardiomyopathy included in their analysis. The variant lies within the myosin head, which is less tolerant to variation (Walsh et al 2016). However, a study that further dissected the regions of the head that are enriched for variation in cases vs. reference samples did not see enrichment at this residue (Homburger et al 2016). There is no variation at 226 codon listed in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Latino, and Ashkenazi descent. I could not find coverage data in gnomAD for this site, however a nearby site appears to be well covered. Note that at this time the gnomAD interface and data are still in beta, with this warning listed “All data on this website should be treated with caution”. There is no variation at codon 226 listed in ExAC, which currently includes variant calls on ~60,000 unrelated individuals of African, Asian, European, Latino, and Ashkenazi descent. The average coverage at that site in ExAC is 100x. -

Jul 19, 2016

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The A226T variant of uncertain significance has been identified in the MYH7 gene. A226T has previously been reported in association with HCM (Bottillo et al., 2016a). In addition, this variant has been identified in one other unrelated individual referred for HCM genetic testing at GeneDx. This variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The A226T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals. Missense variants in nearby residues (Q222K, A223T, L227V) have been reported in the Human Gene Mutation Database in association with cardiomyopathy (Stenson et al., 2014); however, the pathogenicity of these variants has not been definitively determined. Furthermore, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Nevertheless, computational analysis by Bottillo et al. (2016b) predicted that A226T causes steric hindrance, which may lead to functional consequences.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign. -

Hypertrophic cardiomyopathy Pathogenic:1

Dec 21, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 226 of the MYH7 protein (p.Ala226Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of hypertrophic cardiomyopathy (Invitae). ClinVar contains an entry for this variant (Variation ID: 372429). 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 disrupts the p.Ala226 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 27247418, 27532257; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype Pathogenic:1

Mar 06, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.A226T variant (also known as c.676G>A), located in coding exon 6 of the MYH7 gene, results from a G to A substitution at nucleotide position 676. The alanine at codon 226 is replaced by threonine, an amino acid with similar properties. 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). In addition, this alteration has been described in multiple individuals with hypertrophic cardiomyopathy (HCM) (Bottillo I et al. Gene. 2016;577:227-35; Rubattu S et al. Int J Mol Sci, 2016 Jul;17; Ambry internal data; external communication). Another alteration involving the same amino acid, p.A226V (c.677C>T), has also been reported in a HCM cohort (Homburger JR et al. Proc Natl Acad Sci U.S.A. 2016 06;113:6701-6). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
CardioboostCm	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D
Eigen	Uncertain	0.29
Eigen_PC	Benign	0.12
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.56	T
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		0.71
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.62
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.016	D
Polyphen		0.99	D
Vest4		0.86
MutPred		0.39		Gain of catalytic residue at A226 (P = 0.1142);
MVP		0.99
MPC		2.1
ClinPred		0.88	D
GERP RS		3.3
Varity_R		0.62
gMVP		0.90
Mutation Taster		=14/86	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1057517773; hg19: chr14-23900850;