ClinVar Miner

Submissions for variant NM_002471.3(MYH6):c.831G>T (p.Gln277His) (rs140660481)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000172034 SCV000050999 uncertain significance not provided 2013-06-24 criteria provided, single submitter research
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000154662 SCV000204339 uncertain significance not specified 2015-07-07 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The p.Gln277His var iant in MYH6 has been identified by our laboratory in 1 infant with RCM and skel etal myopathy, 1 infant with neonatal-onset RV dilation, and 1 individual with A RVC. This variant has also been identified in 0.2% (24/11576) of Latino chromoso mes by the Exome Aggregation Consortium (ExAC,; dbSNP rs140660481). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, while the clinical significance of the p.Gln277His variant is uncertain, its fre quency suggests that it is more likely to be benign.
Illumina Clinical Services Laboratory,Illumina RCV000358519 SCV000385786 uncertain significance Dilated Cardiomyopathy, Dominant 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000267612 SCV000385787 uncertain significance Hypertrophic cardiomyopathy 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000322673 SCV000385788 uncertain significance Atrial septal defect 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000172034 SCV000557874 likely benign not provided 2019-01-15 criteria provided, single submitter clinical testing
GeneDx RCV000154662 SCV000565717 uncertain significance not specified 2017-06-19 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the MYH6 gene. The Q277H variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. However, this variant has been classified in ClinVar as a variant of uncertain significance by an outside clinical laboratory (ClinVar SCV000204339.3; Landrum et al., 2016). Nevertheless, the Q277H variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, to our knowledge no studies have been performed to determine the functional effect of the Q277H variant. Furthermore, the Exome Aggregation Consortium (ExAC) reports Q277H was observed in 24/11,576 (0.2%) alleles from individuals of Latino background.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000769431 SCV000900824 uncertain significance Cardiomyopathy 2016-08-05 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000154662 SCV000917835 likely benign not specified 2018-05-29 criteria provided, single submitter clinical testing Variant summary: MYH6 c.831G>T (p.Gln277His) results in a non-conservative amino acid change located in the Myosin head, motor domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00037 in 277170 control chromosomes. The observed variant frequency is approximately 15 fold above 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.831G>T has been reported in the literature, however, the report(s) do 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. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 with differing interpretations including VUS (3x) and likely benign (1x). Based on the evidence outlined above, the variant was classified as likely benign.

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