NM_000257.4(MYH7):c.3325A>G (p.Lys1109Glu) AND Hypertrophic cardiomyopathy 1

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: May 6, 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:: RCV000584768.3

Allele description [Variation Report for NM_000257.4(MYH7):c.3325A>G (p.Lys1109Glu)]

NM_000257.4(MYH7):c.3325A>G (p.Lys1109Glu)

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.3325A>G (p.Lys1109Glu)

HGVS:

NC_000014.9:g.23420969T>C
NG_007884.1:g.19693A>G
NM_000257.4:c.3325A>GMANE SELECT
NP_000248.2:p.Lys1109Glu
LRG_384t1:c.3325A>G
LRG_384:g.19693A>G
NC_000014.8:g.23890178T>C
NM_000257.2:c.3325A>G

Protein change:

K1109E

Links:

dbSNP: rs1429196201

NCBI 1000 Genomes Browser:

rs1429196201

Molecular consequence:

NM_000257.4:c.3325A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000692504	Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	criteria provided, single submitter (Agnes Ginges Centre for Molecular Cardiology criteria (2015))	Uncertain significance (Mar 13, 2017)	germline	research	Citation Link,
SCV002767990	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (May 6, 2021)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 24714796, 27532257, 28408708, 29300372, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000692504

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute

criteria provided, single submitter

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

Uncertain significance
(Mar 13, 2017)

germline

research

Citation Link,

SCV002767990

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(May 6, 2021)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

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

Citations

PubMed

Hypertrophic cardiomyopathy: how do mutations lead to disease?

Marsiglia JD, Pereira AC.

Arq Bras Cardiol. 2014 Mar;102(3):295-304. Review. English, Portuguese.

PubMed [citation]

PMID:: 24714796
PMCID:: PMC3987320

Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples.

Walsh R, Thomson KL, Ware JS, Funke BH, Woodley J, McGuire KJ, Mazzarotto F, Blair E, Seller A, Taylor JC, Minikel EV, Exome Aggregation Consortium, MacArthur DG, Farrall M, Cook SA, Watkins H.

Genet Med. 2017 Feb;19(2):192-203. doi: 10.1038/gim.2016.90. Epub 2016 Aug 17.

PubMed [citation]

PMID:: 27532257
PMCID:: PMC5116235

See all PubMed Citations (5)

Details of each submission

From Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, SCV000692504.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	not provided

Description

The MYH7 Lys1109Glu variant has been identified in 1 HCM proband (LMM https://cardiodb.org/ACGV/acgv_variant.php?id=214972). The variant is absent from both the 1000 genomes project (http://www.1000genomes.org/), as well as the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/). We identified this variant in an HCM proband (max LVWT= 18mm) of Filipino descent and one other affected family member (max LVWT= 30mm), who was diagnosed after a syncopal event post-exertion, several months later the individual suffered a resuscitated cardiac arrest after which an ICD was implanted. Computational tools SIFT, PolyPhen-2, PolyPhen-HCM and MutationTaster predict this variant to be deleterious. Based on this limited evidence, we classify MYH7 Lys1109Glu 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 Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002767990.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established, however, missense variants have been proposed to act in a dominant negative manner (PMID: 24714796). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance. Hypertrophic cardiomyopathy is known to be an incompletely penetrant disease, although data specific to this gene is lacking (PMID: 29300372). (I) 0200 - Variant is predicted to result in a missense amino acid change from lysine to glutamic acid. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated myosin tail domain (Pfam). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0803 - This variant has limited previous evidence of pathogenicity in unrelated individuals. The variant was reported as pathogenic in an individual with familial HCM (PMID: 28408708) and as a VUS in three further individuals (two related) with HCM (PMID: 27532257, ClinVar). (SP) 0906 - Segregation evidence for this variant is inconclusive, as it has been reported in two family members with HCM with no further details provided (ClinVar). (I) 1007 - No published functional evidence has been identified for this variant. (I) 1206 - This variant has been shown to be paternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

#	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: Mar 4, 2023

ClinVar

Relating variation to medicine