14-23425774-A-T
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2PM5PP2PP3_Strong
The NM_000257.4(MYH7):c.2207T>A(p.Ile736Asn) variant causes a missense change involving the alteration of a 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I736M) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000257.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 33
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Dec 06, 2013 | The Ile736Asn variant in MYH7 has not been previously reported in individuals wi th cardiomyopathy or in large population studies. This variant was predicted to be benign using a computational tool clinically validated by our laboratory (thi s tool's benign prediction is estimated to be correct 89% of the time; Jordan 20 11). However, additional computational analyses (biochemical amino acid propert ies, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that the variant may impact the protein and another variant at this position (Ile736Thr) is an establ ished pathogenic HCM variant, which suggests that changes affecting isoleucine ( Ile) at position 736 may not be tolerated. In summary, the available information for this variant is somewhat conflicting. Additional information is needed to fully assess its clinical significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at