ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.502G>A (p.Asp168Asn) (rs730880840)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000766402 SCV000208673 uncertain significance not provided 2012-05-29 criteria provided, single submitter clinical testing p.Asp168Asn (GAC>AAC): c.502 G>A in exon 5 of the MYH7 gene (NM_000257.2). The Asp168Asn variant in the MYH7 gene has not been reported previously as a disease-causing mutation nor as a benign polymorphism, to our knowledge. Asp168Asn is a non-conservative amino acid substitution of a negatively charged Aspartic acid with a neutral, polar Asparagine at a residue that is conserved across species. Asp168Asn affects the last nucleotide of exon 5, which is predicted to destroy the canonical splice donor site of intron 5. This variant is predicted to lead to either an abnormal message, which is subjected to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. In addition, the NHLBI ESP Exome Variant Server reports Asp168Asn was not observed in approximately 4,500 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. However, few splice site mutations, or other premature termination codon mutations, have been reported in the MYH7 gene to date. In summary, the clinical significance of the Asp168Asn variant in the MYH7 gene is currently unknown. The variant is found in HCM panel(s).
Invitae RCV000205556 SCV000260017 uncertain significance Hypertrophic cardiomyopathy 2018-02-09 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 168 of the MYH7 protein (p.Asp168Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant also falls at the last nucleotide of exon 5 of the MYH7 coding sequence, which is part of the consensus splice site for this exon. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 27247418). ClinVar contains an entry for this variant (Variation ID: 181308). A computational algorithm designed to assess the pathogenicity of variants in MYH7 with regard to hypertrophic cardiomyopathy predicted this sequence change to be deleterious. The algorithm has a sensitivity of 94% and a specificity of 89% (PMID: 21310275). However, this prediction has not been confirmed by published functional studies and its clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098); however, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in MYH7 cause disease. 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 RCV000158738 SCV000280357 uncertain significance not specified 2013-05-22 no assertion criteria provided clinical testing Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Asp168Asn (D168N, c.502G>A) in the MYH7 gene. This variant is novel. It has not been reported in association with HCM to date. This is a non-conservative amino acid change with a negatively charged Aspartic Acid replaced with a neutral polar Asparagine. The Aspartic Acid is completely conserved at this position across species. The variant affects the last nucleotide of exon 5 and thus is expected to affect the canonical splice donor site of intron 5. This could lead to either an abnormal transcript which is subject to nonsense-mediated mRNA decay and thus no protein product or to an abnormal protein due to abnormal splicing. PolyPhen-2 predicts the variant to be probably damaging, however note that this algorithm does not account for effects on splicing. Mutation taster, which does consider impact on splicing, predicts the variant to be disease causing and notes that it likely disturbs normal splicing. To date no splice variants in MYH7 have been shown to cause hypertrophic cardiomyopathy. However, these variants have also not been observed in general population samples, including the ~6500 individuals sequenced in the NHLBI Exome Sequencing Project. There is some emerging evidence that MYH7 splice variants may cause LVNC. To the best of our knowledge, only one MYH7 splice variant has been reported in association with any cardiomyopathy. Klassen et al (2008) identified c.818+1G>A in two unrelated families (on two different haplotypes) with LVNC. In one family the variant was present in 6 affected family members with the furthest degree of relationship being 4th degree. They reported a LOD score of 2.55 for this family. In the other family the variant segregated with disease in three affected first degree relatives. RT-PCR on lymphocytes consistently revealed the normal transcript with inconsistent production of various aberrant transcripts at very low yield. I checked with the other genetic testing labs and they have each seen one MYH7 splice variant, both in patients with LVNC. We can also consider the possibility that this is a null variant (i.e. no protein product produced), due to nonsense-mediated decay of the abnormal mRNA product(s). The impact of null variants in MYH7 remains unclear. Nearly all reported variants in MYH7 are missense variants. Only a few non-missense variants have been reported and none of these have strong evidence supporting pathogenicity. A few have evidence to suggest they are benign, including failure to segregate with HCM. While the evidence that null MYH7 variants cause disease is currently lacking, they also don’t seem to be well tolerated as they are rare in general population samples. For example, in the NHLBI ESP dataset 2 of ~6500 individuals have a frameshift and 1 of ~6500 individuals have a nonsense variant. Thus it is currently unclear whether null variants in MYH7 can cause HCM. Therefore variants such as nonsense, splicing or frameshift should be considered of uncertain significance until proven otherwise. In total the variant has not been seen in ~6500 publicly available general population samples. Please note that this dataset does not match the patient's ancestry (Hispanic and Native American). GeneDx did not report internal control data. The variant is not listed in dbSNP or 1000 Genomes (as of April 9th, 2013). The variant is not currently listed in the NHLBI Exome Sequencing Project dataset, which includes variant calls on ~6500 Caucasian and African American individuals (as of April 9th, 2013).

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