NM_000257.4(MYH7):c.2389G>A (p.Ala797Thr) AND MYH7-Related Disorders

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Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jan 5, 2022
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:: RCV001813750.4

Allele description

NM_000257.4(MYH7):c.2389G>A (p.Ala797Thr)

Genes:

LOC126861898:BRD4-independent group 4 enhancer GRCh37_chr14:23893609-23894808 [Gene]
MYH7:myosin heavy chain 7 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

14q11.2

Genomic location:

Preferred name:

NM_000257.4(MYH7):c.2389G>A (p.Ala797Thr)

HGVS:

NC_000014.9:g.23425316C>T
NG_007884.1:g.15346G>A
NM_000257.4:c.2389G>AMANE SELECT
NP_000248.2:p.Ala797Thr
LRG_384t1:c.2389G>A
LRG_384:g.15346G>A
NC_000014.8:g.23894525C>T
NM_000257.2:c.2389G>A
NM_000257.3:c.2389G>A
P12883:p.Ala797Thr
c.2389G>A

Protein change:

A797T

Links:

UniProtKB: P12883#VAR_004591; dbSNP: rs3218716

NCBI 1000 Genomes Browser:

rs3218716

Molecular consequence:

NM_000257.4:c.2389G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: MYH7-Related Disorders
Identifiers:: MedGen: CN239297

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002061157	DASA	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 5, 2022)	germline	clinical testing	PubMed (12) [See all records that cite these PMIDs] 31110529, 23233322, 7581410, 18029407, 17125710, 28606303, 22857948, 28138913, 27831900, 24038877, 22975586, 25741868
SCV004014870	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	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

SCV002061157

DASA

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jan 5, 2022)

germline

clinical testing

PubMed (12)
[See all records that cite these PMIDs]

SCV004014870

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic

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	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

The utility of the Mayo Score for predicting the yield of genetic testing in patients with hypertrophic cardiomyopathy.

Bonaventura J, Norambuena P, Tomašov P, Jindrová D, Šedivá H, Macek M Jr, Veselka J.

Arch Med Sci. 2019 May;15(3):641-649. doi: 10.5114/aoms.2018.78767. Epub 2018 Oct 8.

PubMed [citation]

PMID:: 31110529
PMCID:: PMC6524174

Early results of sarcomeric gene screening from the Egyptian National BA-HCM Program.

Kassem HSh, Azer RS, Saber-Ayad M, Moharem-Elgamal S, Magdy G, Elguindy A, Cecchi F, Olivotto I, Yacoub MH.

J Cardiovasc Transl Res. 2013 Feb;6(1):65-80. doi: 10.1007/s12265-012-9425-0. Epub 2012 Dec 12. Erratum in: J Cardiovasc Transl Res. 2013 Aug;6(4):663. Ayad, Maha S [corrected to Saber-Ayad, Maha].

PubMed [citation]

PMID:: 23233322
PMCID:: PMC3546296

See all PubMed Citations (12)

Details of each submission

From DASA, SCV002061157.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (12)

Description

The c.2389G>A;p.(Ala797Thr) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 42901; PMID: 31110529; 23233322; 7581410;18029407;17125710;28606303; 22857948; 28138913; 27831900) - PS4.The variant is located in a mutational hot spot and/or critical and well-established functional domain (IQ) - PM1. The variant is present at low allele frequencies population databases (rs3218716– gnomAD 0.0002629%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. The variant co-segregated with disease in multiple affected family members (PMID: 11186938; 17125710) - PP1_strong. In summary, the currently available evidence indicates that the variant is pathogenic.

#	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

From Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego, SCV004014870.1

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

Description

Missense variation is an established mechanism of disease for MYH7-related disorders (PMID: 7731997, 12975413). The c.2389G>A (p.Ala797Thr) variant affects a weakly conserved amino acid and in silico tools used to predict the effect of this variant on protein function yield discordant results. This variant has been previously reported as a heterozygous change in patients with hypertrophic cardiomyopathy (PMID: 27532257, 7581410, 33673806, 11447480, 24793961, 35653365, 17125710, 33297573, 35288587). In addition, this variant has been previously reported as a heterozygous change in onepatient with Wolff-Parkinson-White syndrome (PMID: 32233023). The c.2389G>A (p.Ala797Thr) variant is located in a mutational hotspot for pathogenic variations associated with hypertrophic cardiomyopathy (PMID: 27532257). The c.2389G>A (p.Ala797Thr) variant is presentin the heterozygous state in the gnomAD population database at a frequency of 0.002% (6/251468) and is absent in the homozygous state, thus is presumed to be rare. Based on the available evidence, c.2389G>A (p.Ala797Thr) is classified as Pathogenic.

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

Last Updated: May 7, 2024

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