NM_002471.4(MYH6):c.1753G>A (p.Gly585Ser) AND not specified

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Aug 17, 2020
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:: RCV000037446.7

Allele description [Variation Report for NM_002471.4(MYH6):c.1753G>A (p.Gly585Ser)]

NM_002471.4(MYH6):c.1753G>A (p.Gly585Ser)

Gene:

MYH6:myosin heavy chain 6 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

14q11.2

Genomic location:

Preferred name:

NM_002471.4(MYH6):c.1753G>A (p.Gly585Ser)

HGVS:

NC_000014.9:g.23398866C>T
NG_023444.1:g.14412G>A
NM_002471.4:c.1753G>AMANE SELECT
NP_002462.2:p.Gly585Ser
NP_002462.2:p.Gly585Ser
LRG_389t1:c.1753G>A
LRG_389:g.14412G>A
LRG_389p1:p.Gly585Ser
NC_000014.8:g.23868075C>T
NM_002471.3:c.1753G>A
c.1753G>A

Protein change:

G585S

Links:

dbSNP: rs150415679

NCBI 1000 Genomes Browser:

rs150415679

Molecular consequence:

NM_002471.4:c.1753G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

Recent activity

Clear Turn Off Turn On

CCL15 C-C motif chemokine ligand 15 [Homo sapiens]
CCL15 C-C motif chemokine ligand 15 [Homo sapiens]
Gene ID:6359

Gene

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
SCV000052972	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Aug 17, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV000061104	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Uncertain significance (Mar 11, 2014)	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

SCV000052972

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(Aug 17, 2020)

germline

clinical testing

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

Citation Link,

SCV000061104

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Uncertain significance
(Mar 11, 2014)

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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	2	2	not provided	not provided	not provided	clinical testing

Citations

PubMed

Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands.

Jin SC, Homsy J, Zaidi S, Lu Q, Morton S, DePalma SR, Zeng X, Qi H, Chang W, Sierant MC, Hung WC, Haider S, Zhang J, Knight J, Bjornson RD, Castaldi C, Tikhonoa IR, Bilguvar K, Mane SM, Sanders SJ, Mital S, Russell MW, et al.

Nat Genet. 2017 Nov;49(11):1593-1601. doi: 10.1038/ng.3970. Epub 2017 Oct 9.

PubMed [citation]

PMID:: 28991257
PMCID:: PMC5675000

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]

PMID:: 24033266
PMCID:: PMC3995020

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000052972.3

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

Description

Variant summary: MYH6 c.1753G>A (p.Gly585Ser) results in a non-conservative amino acid change located in the Myosin head, motor domain (IPR001609) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00015 in 251460 control chromosomes (gnomAD). The observed variant frequency is approximately 6 fold of the estimated maximal expected allele frequency for a pathogenic variant in MYH6 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is benign. c.1753G>A has been reported in the literature in at least one individual affected with congenital heart disease (CHD). This report however, does not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three other ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly 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

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000061104.5

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

Description

The Gly585Ser variant in MYH6 has now been identified by our laboratory in one C aucasian adult with RCM, who carried a pathogenic variant in another RCM associa ted gene, and one individual with ischemic cardiomyopathy and congestive heart f ailure. This variant has also been identified in 3/8600 of European American chr omosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS /; dbSNP rs150415679). Computational prediction tools and conservation analyses suggest that the Gly585Ser variant may impact the protein, though this informati on is not predictive enough to determine pathogenicity. In summary, additional i nformation is needed to fully assess its clinical significance.

#	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		2	not provided	2	not provided

Last Updated: May 1, 2024

ClinVar

Relating variation to medicine