NM_000257.4(MYH7):c.2717A>G (p.Asp906Gly) AND not provided

Germline classification:: Pathogenic (6 submissions)
Last evaluated:: Aug 6, 2024
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:: RCV000158569.23

Allele description [Variation Report for NM_000257.4(MYH7):c.2717A>G (p.Asp906Gly)]

NM_000257.4(MYH7):c.2717A>G (p.Asp906Gly)

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.2717A>G (p.Asp906Gly)

Other names:

NM_000257.3(MYH7):c.2717A>G

HGVS:

NC_000014.9:g.23424112T>C
NG_007884.1:g.16550A>G
NM_000257.4:c.2717A>GMANE SELECT
NP_000248.2:p.Asp906Gly
LRG_384t1:c.2717A>G
LRG_384:g.16550A>G
NC_000014.8:g.23893321T>C
NM_000257.2:c.2717A>G
NM_000257.3:c.2717A>G
P12883:p.Asp906Gly
c.2717A>G

Protein change:

D906G; ASP906GLY

Links:

UniProtKB: P12883#VAR_042814; OMIM: 160760.0039; dbSNP: rs267606908

NCBI 1000 Genomes Browser:

rs267606908

Molecular consequence:

NM_000257.4:c.2717A>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Functional Laterality
Functional Laterality
Behavioral manifestations of cerebral dominance in which there is preferential use and superior functioning of either the left or the right side, as in the preferred use of th...<br/>Year introduced: 2007(1966)

MeSH
Filaricides [Pharmacological Action]
Filaricides [Pharmacological Action]

MeSH
HEXB hexosaminidase subunit beta [Sus scrofa]
HEXB hexosaminidase subunit beta [Sus scrofa]
Gene ID:396958

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000208504	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Aug 6, 2024)	germline	clinical testing	Citation Link,
SCV000280333	Stanford Center for Inherited Cardiovascular Disease, Stanford University	no assertion criteria provided	Pathogenic (Jan 16, 2012)	germline	clinical testing
SCV000861540	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL ClinVar v180209 classification definitions)	Pathogenic (May 25, 2018)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 12081993, 15528230, 27247418, 27532257 Citation Link,
SCV001715068	Mayo Clinic Laboratories, Mayo Clinic	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 21, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002017667	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 6, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002051556	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 4, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

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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	clinical testing
not provided	germline	unknown	3	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	9	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Assessment of diastolic function with Doppler tissue imaging to predict genotype in preclinical hypertrophic cardiomyopathy.

Ho CY, Sweitzer NK, McDonough B, Maron BJ, Casey SA, Seidman JG, Seidman CE, Solomon SD.

Circulation. 2002 Jun 25;105(25):2992-7.

PubMed [citation]

PMID:: 12081993

Molecular and phenotypic effects of heterozygous, homozygous, and compound heterozygote myosin heavy-chain mutations.

Alpert NR, Mohiddin SA, Tripodi D, Jacobson-Hatzell J, Vaughn-Whitley K, Brosseau C, Warshaw DM, Fananapazir L.

Am J Physiol Heart Circ Physiol. 2005 Mar;288(3):H1097-102. Epub 2004 Nov 4.

PubMed [citation]

PMID:: 15528230

See all PubMed Citations (5)

Details of each submission

From GeneDx, SCV000208504.11

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

Description

Not observed at significant frequency in large population cohorts (gnomAD); A functional study demonstrated that this missense variant caused myosin to move actin at an increased velocity compared to control (PMID: 15528230); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28166811, 27532257, 28606303, 24704860, 29300372, 15528230, 28481356, 29203298, 34542152, 23054336, 12081993, 16267253, 24510615, 26914223, 27247418, 21310275, 28193612, 28241245, 31006259, 32894683, 33087929, 36252119, 36264615, 37652022, 36136372, 36129056)

#	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 Stanford Center for Inherited Cardiovascular Disease, Stanford University, SCV000280333.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	9	not provided	not provided	clinical testing	not provided

Description

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. MYH7 p.Asp906Gly (c.2717A>G) Given the strong case data, strong segregation data, and absence in controls and the general population (reviewed below) we consider this variant very likely disease causing. The variant has been seen in at least 9 unrelated cases of HCM (not including this patient's family). There is strong segregation data. The Seidmans’ group included a kindred with this variant in a study on diastolic dysfunction in HCM (Ho et al 2002). Of 22 carriers studied, 9 had HCM. Alpert et al (2005) reported a family with this variant with 3 of 13 carriers having HCM. Two siblings from this family married two siblings from another family with HCM and a different MYH7 variant. Two offspring carried both variants and both had HCM. The Seidman group later reported a patient with apical HCM and this variant. His brother died suddenly and had evidence of HCM on autopsy (Arad et al 2005). This appears to be a different family than reported in Ho et al (2002). Ackerman's group observed the variant in 4 patients in their cohort of 1053 unrelated patients with HCM who underwent DHLPC-based analysis of 9 sarcomere genes at Mayo (Bos et al 2014). Those cases are presumably redundant with those in another paper by Ackerman’s group that included 5 HCM patients seen at Mayo or tested Transgenomics (Kapplinger et al 2014). McKenna’s group included a patient with HCM and this variant from their UK cohort in a paper on developmental structural differences in HCM (Captur et al 2014). Per their ClinVar submission, LMM considers the variant pathogenic (SCV000059468). The submission does not include any internal case data. 2 additional entries in ClinVar (OMIM and GeneDx) consider this variant pathogenic. In silico analysis with PolyPhen-2 predicts the variant to be benign (HumVar score 0.375). Mutationtaster predicts it to be disease causing. The aspartate at codon 906 is not completely conserved across species. Other variants have been reported in association with disease at this codon (p.Asp906Asn (per ClinVar, LMM considers this of uncertain significance (SCV000059466, last reviewed by LMM in 2010)) and nearby codons (p.Asp900Gly, p.Gln907Lys, p.Leu908Val, p.Ile909Val). In total the variant has not been seen in ~6700 published controls and individuals from publicly available population datasets. There is no variation at codon 906 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6500 Caucasian and African American individuals (as of October 3rd, 2014). Additionally, there is no variation at this codon in the ExAC dataset, which contains sequence data from ~65,000 individuals of varying ancestries from various exome sequencing cohorts (as of Feb 26, 2015). The variant is listed in dbSNP (rs267606908) with the only submission being disease-related (as of October 3rd, 2014). There is also no variation at this codon listed 1000 genomes (as of October 3rd, 2014). The variant was not observed in the following published control samples: 200 (Bos et al 2014).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		9	not provided	not provided	not provided

From Eurofins Ntd Llc (ga), SCV000861540.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (4)

#	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		1	not provided	not provided	not provided

From Mayo Clinic Laboratories, Mayo Clinic, SCV001715068.2

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

Description

PP1_strong, PP3, PM1, PM2, PS4

#	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		2	not provided	not provided	not provided

From Revvity Omics, Revvity, SCV002017667.3

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

#	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

From Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center, SCV002051556.3

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

Description

PS4, PM1, PM2

#	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: Nov 3, 2024

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