rs727504844
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2
The NM_000257.4(MYH7):c.5110C>T(p.Gln1704*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,718 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000257.4 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MYH7 | NM_000257.4 | c.5110C>T | p.Gln1704* | stop_gained | Exon 35 of 40 | ENST00000355349.4 | NP_000248.2 | |
MYH7 | NM_001407004.1 | c.5110C>T | p.Gln1704* | stop_gained | Exon 34 of 39 | NP_001393933.1 | ||
MHRT | NR_126491.1 | n.108G>A | non_coding_transcript_exon_variant | Exon 2 of 6 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461718Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1AN XY: 727148
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not specified Uncertain:1
Variant classified as Uncertain Significance - Favor Pathogenic. The Gln1704X va riant in MYH7 has not been reported in individuals with cardiomyopathy or in lar ge European American and African American populations (NHLBI exome sequencing pr oject). This nonsense variant leads to a premature termination codon at position 1704, which is predicted to lead to a truncated or absent protein. It should be noted that loss of function variants in the MYH7 gene are very rare and therefo re, their phenotypic spectrum is unknown. In the few reported cases with MYH7 no nsense variants, all were present in trans along with another MYH7 variant in a severely affected, young individual and in all cases the nonsense variant was in herited from an unaffected parent, suggesting that heterozygous loss of function of MYH7 may not be disease causing (Houghs 2005, Nishi 1995, LMM unpublished da ta). In summary, although this variant severely impacts the protein, additional studies are needed to fully assess its clinical significance. -
not provided Uncertain:1
p.Gln1704Stop (CAG>TAG): c.5110 C>T in exon 35 of the MYH7 gene (NM_000257.2). The Gln1704Stop variant in the MYH7 gene has not been reported as a disease-causing mutation or as benign polymorphism to our knowledge. Gln1704Stop is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. Although nonsense mutations in the MYH7 gene have been reported in association with cardiomyopathy, the vast majority of mutations in MYH7 are missense changes. Furthermore, various studies have conflicting hypotheses regarding MYH7 haploinsufficiency leading to cardiomyopathy (Nishi H et al., 1995; Waldmuller S et al., 2011). With the clinical and molecular information available at this time, we cannot definitively determine if Gln1704Stop is a disease-causing mutation or a rare benign variant. The variant is found in DCM panel(s). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at