NM_000257.4(MYH7):c.4954G>T (p.Asp1652Tyr) AND Hypertrophic cardiomyopathy 1

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Sep 23, 2021
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000584779.3

Allele description [Variation Report for NM_000257.4(MYH7):c.4954G>T (p.Asp1652Tyr)]

NM_000257.4(MYH7):c.4954G>T (p.Asp1652Tyr)

Genes:

LOC126861897:BRD4-independent group 4 enhancer GRCh37_chr14:23884455-23885654 [Gene]
MYH7:myosin heavy chain 7 [Gene - OMIM - HGNC]
MHRT:myosin heavy chain associated RNA transcript [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

14q11.2

Genomic location:

Preferred name:

NM_000257.4(MYH7):c.4954G>T (p.Asp1652Tyr)

HGVS:

NC_000014.9:g.23415832C>A
NG_007884.1:g.24830G>T
NM_000257.4:c.4954G>TMANE SELECT
NP_000248.2:p.Asp1652Tyr
LRG_384t1:c.4954G>T
LRG_384:g.24830G>T
NC_000014.8:g.23885041C>A
NM_000257.2:c.4954G>T
NM_000257.3:c.4954G>T
c.4954G>T

Protein change:

D1652Y

Links:

dbSNP: rs397516233

NCBI 1000 Genomes Browser:

rs397516233

Molecular consequence:

NM_000257.4:c.4954G>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Hypertrophic cardiomyopathy 1
Synonyms:: Familial hypertrophic cardiomyopathy 1; MYH7-Related Familial Hypertrophic Cardiomyopathy
Identifiers:: MONDO: MONDO:0008647; MedGen: C3495498; OMIM: 192600

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000692493	Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	criteria provided, single submitter (Agnes Ginges Centre for Molecular Cardiology criteria (2015))	Uncertain significance (Mar 9, 2017)	germline	research	PubMed (2) [See all records that cite these PMIDs] 19659763, 21302287 Citation Link,
SCV002765157	Servicio Canario de Salud, Hospital Universitario Nuestra Sra. de Candelaria	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Sep 23, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000692493

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute

criteria provided, single submitter

(Agnes Ginges Centre for Molecular Cardiology criteria (2015))

Uncertain significance
(Mar 9, 2017)

germline

research

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV002765157

Servicio Canario de Salud, Hospital Universitario Nuestra Sra. de Candelaria

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Sep 23, 2021)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	research
caucasian	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A child cohort study from southern Italy enlarges the genetic spectrum of hypertrophic cardiomyopathy.

Frisso G, Limongelli G, Pacileo G, Del Giudice A, Forgione L, Calabrò P, Iacomino M, Detta N, Di Fonzo LM, Maddaloni V, Calabrò R, Salvatore F.

Clin Genet. 2009 Jul;76(1):91-101. doi: 10.1111/j.1399-0004.2009.01190.x.

PubMed [citation]

PMID:: 19659763

Unexpectedly low mutation rates in beta-myosin heavy chain and cardiac myosin binding protein genes in Italian patients with hypertrophic cardiomyopathy.

Roncarati R, Latronico MV, Musumeci B, Aurino S, Torella A, Bang ML, Jotti GS, Puca AA, Volpe M, Nigro V, Autore C, Condorelli G.

J Cell Physiol. 2011 Nov;226(11):2894-900. doi: 10.1002/jcp.22636.

PubMed [citation]

PMID:: 21302287
PMCID:: PMC3229838

See all PubMed Citations (3)

Details of each submission

From Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, SCV000692493.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (2)

Description

This MYH7 Asp1652Tyr variant has been described in two Italian HCM patients (Frisso G, et al., 2009; Roncarati R, et al., 2011). Segregation analysis provided by Frisso G et al. (2009) identified two family members who also carry this variant. Both members however, did not have typical HCM characteristics but rather a dilated (proband's sister) and restrictive (proband's father) cardiomyopathy phenotype. We have identified this MYH7 Asp1652Tyr variant in an isolated HCM patient of North West European descent. Clinical screening of the family revealed no family history of HCM and/or sudden cardiac death. We note that additional uncertain variants have been identified in the proband which may contribute to the disease phenotype (MYL2 Ala13Thr; DSG2 Asp535Glu). The MYH7 Asp1652Tyr variant is absent in 1000 genomes project (http://www.1000genomes.org/), and has a frequency of 0.00002475 in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/). Aspartic acid at position 1652 is highly conserved across distantly related species, and computational tools predict the Asp1652Tyr to be "deleterious" (SIFT) and "disease-causing" (MutationTaster). Additionally, Polyphen_HCM (Jordan DM, et al., 2011) predicts that this MYH7 Asp1652Tyr variant is causative of the disease. Based on this information, we classify MYH7 Asp1652Tyr as a variant of "uncertain significance".

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Servicio Canario de Salud, Hospital Universitario Nuestra Sra. de Candelaria, SCV002765157.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	caucasian	1	not provided	not provided	clinical testing	PubMed (1)

Description

The c.4954G>T (p.Asp1652Tyr) MYH7 variant has been reported in our laboratory in a 44-year-old patient with diagnosis of hypertrophic cardiomyopathy. Mother (with permanent atrial fibrillation and pacemaker) and maternal grandmother with the same diagnosis. This variant is present in population databases (gnomAD allele frequency 0.00004774, 12/251342 alleles) being more frequent in the Latino population (gnomAD allele frequency 0.0001446). This variant has been previously reported in a patients with hypertrophic cardiomyopathy [PMID 28790153, 27247418, 27532257, 28356264]. ClinVar contains an entry for this variant (Variation ID: 43047). In silico analysis (CADD, Mutation Taster, SIFT, Provean, PolyPhen2) supports that this missense variant has a deleterious effect on protein structure/function. Some in silico splicing studies predict that it affects the natural splicing acceptor of intron 34, but there are no in vitro or in vivo functional studies, as well as RNA studies that have verified this aspect. In summary, c.4954G>T (p.Asp1652Tyr) MYH7 variant is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Oct 8, 2024

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