ClinVar Miner

Submissions for variant NM_000432.3(MYL2):c.308T>G (p.Phe103Cys) (rs547860537)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Human Development Section,National Institutes of Health RCV000172054 SCV000054782 uncertain significance not provided 2013-06-24 criteria provided, single submitter research
GeneDx RCV000172054 SCV000208862 likely pathogenic not provided 2012-06-26 criteria provided, single submitter clinical testing p.Phe103Cys (TTC>TGC): c.308 T>G in exon 5 of the MYL2 gene (NM_000432.3)The Phe103Cys variant in the MYL2 gene has not been reported previously as a disease-causing mutation nor as a benign polymorphism, to our knowledge. Phe103Cys results in a non-conservative amino acid substitution of a non-polar Phenylalanine with a neutral, polar Cysteine at a residue that is conserved across species. The NHLBI ESP Exome Variant Server reports Phe103Cys was not observed in approximately 5,000 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. However, the only nearby putative mutation (Lys104Glu) in this region of MYL2 was also identified in an individual with HCM who harbored a definitive splice site mutation in the MYL2 gene, leaving the clinical significance of the missense change unclear (Andersen P et al., 2001). In summary, the clinical significance of Phe103Cys in the MYL2 gene is currently unknown. The variant is found in HCM panel(s).
Invitae RCV000467685 SCV000549159 uncertain significance Familial hypertrophic cardiomyopathy 10 2017-04-11 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with cysteine at codon 103 of the MYL2 protein (p.Phe103Cys). The phenylalanine residue is highly conserved and there is a large physicochemical difference between phenylalanine and cysteine. This variant is present in population databases (rs547860537, ExAC 0.09%) but has not been reported in the literature in individuals with a MYL2-related disease. ClinVar contains an entry for this variant (Variation ID: 181433). 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 disruptive, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change with uncertain impact on protein function. Because it is found in the population at an appreciable frequency, this variant is not anticipated to cause disease. However, the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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