rs397516097

chr14-23429089-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP2 PP3_Strong PP5

The NM_000257.4(MYH7):c.1273G>A(p.Gly425Arg) 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. G425A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYH7 NM_000257.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2
• Conservation: PhyloP100: 3.32

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 Pathogenic. Variant got 10 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 12 uncertain in NM_000257.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, MYH7
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.982
• PP5: Variant 14-23429089-C-T is Pathogenic according to our data. Variant chr14-23429089-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 42834.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=2}. Variant chr14-23429089-C-T is described in Lovd as [Pathogenic]. Variant chr14-23429089-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH7	NM_000257.4	c.1273G>A	p.Gly425Arg	missense_variant	14/40	ENST00000355349.4
MYH7	NM_001407004.1	c.1273G>A	p.Gly425Arg	missense_variant	13/39

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH7	ENST00000355349.4	c.1273G>A	p.Gly425Arg	missense_variant	14/40	1	NM_000257.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypertrophic cardiomyopathy Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 05, 2019	proposed classification - variant undergoing re-assessment, contact laboratory -
Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Mar 14, 2022	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. 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). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 42834). This missense change has been observed in individuals with clinical features of MYH7-related conditions (PMID: 15563892, 19586842, 27247418, 29497013, 32931854; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 425 of the MYH7 protein (p.Gly425Arg). -

not specified Uncertain:1

Uncertain significance, flagged submission

clinical testing

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Feb 24, 2015

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.Gly425Arg (c.1273G>A) in the MYH7 gene. The patient's genetic test results were first reviewed in 2007. They were re-reviewed 1/31/12, 5/15/13, and 17 March 2015. This variant has been reported in at least two cases of HCM (not including our patient) with moderate segregation data and seen in an additional case with a family history of HCM. Song et al (2005) reported the variant in one case of HCM with no segregation data provided. The same group reported a family with four individuals with p.Gly425Arg (Wang et al 2009). Unfortunately that publication is in Chinese, so it is difficult to assess whether it is the same family. We did have a member of our team who reads Chinese review the paper and found that the variant was seen in three family members with HCM and one obligate carrier. There is an assertion in ClinVar as likely pathogenic, from LMM (SCV000059363). They do not note any additional case data and they have not reviewed it since 2010. I contacted them and they shared that they have seen it in one unaffected individual with a family history of HCM, they have not tested any affected individuals. GeneDx also has an assertion in ClinVar, as pathogenic. Other variants at nearby codons have been reported in association with HCM: p.Ala428Val, (Richard et al., 2003; Van Driest et al., 2004), p.Ala430Glu (Morner et al., 2003), and p. Met435Thr (Sawyer et al., 2003). This is a non-conservative amino acid change with a non-polar neutral Glycine replaced with a polar positive Arginine. Glycine at codon 425 is completely conserved in MYH7 across species. In silico analysis (PolyPhen 2) predicts the variant to be probably damaging. In ClinVar LMM notes that their in-house computational tool predicts it to be pathogenic (and is correct 94% of the time) (Jordan et al 2011). The variant was not observed in a total of ~64,120 published and publicly available general population samples, with ~4420 of those matching this patient's ancestry (and the ancestry of the published cases). Specifically, this variant was not observed in 120 published Chinese control individuals (Song et al 2005). This is likely the same 120 control individuals reported by Wang et al (2009). The variant is not reported in dbSNP or 1000 genomes (as of 5/15/13.) There is no variation at codon 425 listed 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 January 21st, 2015). This includes ~4300 Easy Asian individuals. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 04, 2023

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at significant frequency in large population cohorts (gnomAD); Identified in patients with cardiomyopathy referred for genetic testing at GeneDx and in published literature (Song et al., 2005; Wang et al., 2009; Homburger et al., 2016; Mak et al., 2018); This variant is associated with the following publications: (PMID: 27247418, 19586842, 15563892, 32931854, 29497013, 27532257, 29300372, 34949102, 31856055) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
CardioboostCm	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Uncertain	2.7	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-5.9	D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.049	D
Polyphen		1.0	D
Vest4		0.88
MutPred		0.81		Gain of MoRF binding (P = 0.0045);
MVP		0.98
MPC		2.3
ClinPred		0.99	D
GERP RS		4.0
Varity_R		0.96
gMVP		0.99

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: rs397516097; hg19: chr14-23898298; COSMIC: COSV104668943;