rs397516755

chr14-23400412-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_002471.4(MYH6):c.1425G>C(p.Glu475Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYH6 NM_002471.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.90

Genes affected

MYH6 (HGNC:7576): (myosin heavy chain 6) Cardiac muscle myosin is a hexamer consisting of two heavy chain subunits, two light chain subunits, and two regulatory subunits. This gene encodes the alpha heavy chain subunit of cardiac myosin. The gene is located approximately 4kb downstream of the gene encoding the beta heavy chain subunit of cardiac myosin. Mutations in this gene cause familial hypertrophic cardiomyopathy and atrial septal defect 3. [provided by RefSeq, Feb 2017]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, MYH6
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.902

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH6	NM_002471.4	c.1425G>C	p.Glu475Asp	missense_variant	14/39	ENST00000405093.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH6	ENST00000405093.9	c.1425G>C	p.Glu475Asp	missense_variant	14/39	5	NM_002471.4	P1
MYH6	ENST00000557461.2	n.1492G>C		non_coding_transcript_exon_variant	14/14	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 13, 2012

The Glu475Asp variant (MYH6) has not been reported in the literature nor previou sly identified by our laboratory. Glutamic acid (Glu) at this position in conse rved across evolutionarily distant species, suggesting that a change may not be tolerated. Computational analysis (AlignGVGD, SIFT, PolyPhen2) suggest that thi s change may impact protein function; however, the accuracy of these tools is un known. In summary, additional information is needed to determine the clinical s ignificance of this variant. -

MYH6-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 23, 2023

The MYH6 c.1425G>C variant is predicted to result in the amino acid substitution p.Glu475Asp. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.84	D;D
Eigen	Benign	-0.028
Eigen_PC	Benign	-0.018
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.96	D;.
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.90	D;D
MetaSVM	Uncertain	0.33	D
MutationAssessor	Uncertain	2.8	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-2.5	N;N
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0090	D;D
Sift4G	Uncertain	0.016	D;D
Polyphen		0.0020	B;B
Vest4		0.95
MutPred		0.78		Gain of catalytic residue at F471 (P = 0.0041);Gain of catalytic residue at F471 (P = 0.0041);
MVP		0.89
MPC		0.37
ClinPred		0.73	D
GERP RS		2.2
Varity_R		0.28
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs397516755; hg19: chr14-23869621;