ClinVar Miner

Submissions for variant NM_003803.3(MYOM1):c.814C>T (p.His272Tyr) (rs1555628272)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000629006 SCV000749916 uncertain significance Hypertrophic cardiomyopathy 2017-12-07 criteria provided, single submitter clinical testing This sequence change replaces histidine with tyrosine at codon 272 of the MYOM1 protein (p.His272Tyr). The histidine residue is weakly conserved and there is a moderate physicochemical difference between histidine and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MYOM1-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000786375 SCV000925183 uncertain significance not provided 2018-01-21 no assertion criteria provided provider interpretation Variant p.His272Tyr in MYOM1 c.814C>T in exon 5 of MYOM1 (NM_003803.3, hg19, chr18-3187593-G-A) SCICD classification Variant of uncertain significance We do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The rationale for this assessment is: lack of data to associate MYOM1 with HCM, the lack of data on this particular variant and its co-occurrence with a pathogenic variant in the same patient. Gene-level evidence MYOM1: MYOM1 encodes myomesin, a protein located in the M band of sarcomeres and is expressed in several isoforms of striated muscle. Myomesin dimers cross-link myosin (in the N-terminal domain 1) and titin (domains 4-6). Siegert et al (2011) identified a missense variant in MYOM1 in a proband with HCM. It segregated with disease in two other relatives. Per the ExAC database, MYOM1 appears to be tolerant of both missense (z=-0.35) and loss of function (pLI=0.00) variation. Given the lack of data to support the role of MYOM1 in HCM, we consider it a gene of uncertain significance. Case data summary Not reported in the literature. Not listed in ClinVar. Predicted Consequence Per the test report, "This sequence change replaces histidine with tyrosine at codon 272 of the MYOM1 protein (p.His272Tyr)." Experimental Data None reported In silico data Per the test report, "Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain." Conservation Per the test report, "The histidine residue is weakly conserved and there is a moderate physicochemical difference between histidine and tyrosine." The histidine at codon 272 is conserved in 37 of 100 total aligned species in the UCSC genome browser. It is weakly conserved. Nearby pathogenic variation There is no pathogenic variation listed at this codon or nearby codons in ClinVar. Population Data There is no variation at this codon in gnomAD. Metrics indicate adequate coverage. Please see below for details. Population data for p.His272Tyr in MYOM1: There is no variation at codon 272 listed in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Latino, and Ashkenazi descent. As of January 21, 2018 the average coverage at that site in gnomAD for exomes is: Mean coverage 63.2x, Median coverage 66x, and 97.53% of samples over 20x coverage.

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