rs730880840

Positions:

• chr14-23432639-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP3_Moderate

The NM_000257.4(MYH7):​c.502G>A​(p.Asp168Asn) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000684 in 1,461,882 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MYH7 NM_000257.4 missense, splice_region
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 5.95

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 helix (size 14) in uniprot entity MYH7_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_000257.4
• PM2: Very rare variant in population databases, with high coverage
• 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: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH7	NM_000257.4	c.502G>A	p.Asp168Asn	missense_variant, splice_region_variant	5/40	ENST00000355349.4	NP_000248.2
MYH7	NM_001407004.1	c.502G>A	p.Asp168Asn	missense_variant, splice_region_variant	4/39		NP_001393933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4	c.502G>A	p.Asp168Asn	missense_variant, splice_region_variant	5/40	1	NM_000257.4	ENSP00000347507	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461882 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727244

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Stanford Center for Inherited Cardiovascular Disease, Stanford University

May 22, 2013

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.Asp168Asn (D168N, c.502G>A) in the MYH7 gene. This variant is novel. It has not been reported in association with HCM to date. This is a non-conservative amino acid change with a negatively charged Aspartic Acid replaced with a neutral polar Asparagine. The Aspartic Acid is completely conserved at this position across species. The variant affects the last nucleotide of exon 5 and thus is expected to affect the canonical splice donor site of intron 5. This could lead to either an abnormal transcript which is subject to nonsense-mediated mRNA decay and thus no protein product or to an abnormal protein due to abnormal splicing. PolyPhen-2 predicts the variant to be probably damaging, however note that this algorithm does not account for effects on splicing. Mutation taster, which does consider impact on splicing, predicts the variant to be disease causing and notes that it likely disturbs normal splicing. To date no splice variants in MYH7 have been shown to cause hypertrophic cardiomyopathy. However, these variants have also not been observed in general population samples, including the ~6500 individuals sequenced in the NHLBI Exome Sequencing Project. There is some emerging evidence that MYH7 splice variants may cause LVNC. To the best of our knowledge, only one MYH7 splice variant has been reported in association with any cardiomyopathy. Klassen et al (2008) identified c.818+1G>A in two unrelated families (on two different haplotypes) with LVNC. In one family the variant was present in 6 affected family members with the furthest degree of relationship being 4th degree. They reported a LOD score of 2.55 for this family. In the other family the variant segregated with disease in three affected first degree relatives. RT-PCR on lymphocytes consistently revealed the normal transcript with inconsistent production of various aberrant transcripts at very low yield. I checked with the other genetic testing labs and they have each seen one MYH7 splice variant, both in patients with LVNC. We can also consider the possibility that this is a null variant (i.e. no protein product produced), due to nonsense-mediated decay of the abnormal mRNA product(s). The impact of null variants in MYH7 remains unclear. Nearly all reported variants in MYH7 are missense variants. Only a few non-missense variants have been reported and none of these have strong evidence supporting pathogenicity. A few have evidence to suggest they are benign, including failure to segregate with HCM. While the evidence that null MYH7 variants cause disease is currently lacking, they also don’t seem to be well tolerated as they are rare in general population samples. For example, in the NHLBI ESP dataset 2 of ~6500 individuals have a frameshift and 1 of ~6500 individuals have a nonsense variant. Thus it is currently unclear whether null variants in MYH7 can cause HCM. Therefore variants such as nonsense, splicing or frameshift should be considered of uncertain significance until proven otherwise. In total the variant has not been seen in ~6500 publicly available general population samples. Please note that this dataset does not match the patient's ancestry (Hispanic and Native American). GeneDx did not report internal control data. The variant is not listed in dbSNP or 1000 Genomes (as of April 9th, 2013). The variant is not currently listed in the NHLBI Exome Sequencing Project dataset, which includes variant calls on ~6500 Caucasian and African American individuals (as of April 9th, 2013). -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 29, 2012

p.Asp168Asn (GAC>AAC): c.502 G>A in exon 5 of the MYH7 gene (NM_000257.2). The Asp168Asn variant in the MYH7 gene has not been reported previously as a disease-causing mutation nor as a benign polymorphism, to our knowledge. Asp168Asn is a non-conservative amino acid substitution of a negatively charged Aspartic acid with a neutral, polar Asparagine at a residue that is conserved across species. Asp168Asn affects the last nucleotide of exon 5, which is predicted to destroy the canonical splice donor site of intron 5. This variant is predicted to lead to either an abnormal message, which is subjected to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. In addition, the NHLBI ESP Exome Variant Server reports Asp168Asn was not observed in approximately 4,500 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. However, few splice site mutations, or other premature termination codon mutations, have been reported in the MYH7 gene to date. In summary, the clinical significance of the Asp168Asn variant in the MYH7 gene is currently unknown. The variant is found in HCM panel(s). -

Hypertrophic cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 10, 2023

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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 181308). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 27247418). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 168 of the MYH7 protein (p.Asp168Asn). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
CardioboostCm	Pathogenic	0.99
BayesDel_addAF	Benign	-0.013	T
BayesDel_noAF	Benign	-0.26
CADD	Pathogenic	35
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	D
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.84	T
M_CAP	Pathogenic	0.81	D
MetaRNN	Uncertain	0.69	D
MetaSVM	Uncertain	0.14	D
MutationAssessor	Benign	0.30	N
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-1.0	N
REVEL	Uncertain	0.47
Sift	Benign	0.35	T
Sift4G	Benign	0.46	T
Polyphen		1.0	D
Vest4		0.45
MutPred		0.58		Gain of catalytic residue at Q163 (P = 0.0152);
MVP		0.89
MPC		2.1
ClinPred		0.99	D
GERP RS		3.3
Varity_R		0.28
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.070		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: rs730880840; hg19: chr14-23901848;