rs564101364
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PP1PP3PM2_SupportingPS4_Moderate
This summary comes from the ClinGen Evidence Repository: The NM_000257.4(MYH7):c.1633G>A (p.Asp545Asn) variant has been identified in cis with with another MYH7 variant (NM_000257.4:c.2863G>A (p.Asp955Asn)) in at least 5 individuals with DCM, two of whom also had LVNC and in isolation in 1 individual with DCM (PS4_Moderate: van den Berg 2010 PMID:20952769, van Spaendonck-Zwarts 2013 PMID:23349452, Invitae pers. comm., Ambry pers. comm.). The combination of MYH7 variants were also identified in 1 individual with LVNC (Hoedemaekers 2007 PMID:17947214) and 1 individual with ARVC (Invitae pers. comm). Additionally, both MYH7 variants segregated with DCM in 3 affected relatives from 1 family (PP1: van den Berg 2010 PMID:20952769) and with LVNC in 4 affected relatives from another family (Hoedemaekers 2007 PMID:17947214). While this variant has been reported in multiple phenotypes, there is conflicting evidence on whether isolated LVNC is a Mendelian disease and therefore those cases without additional cardiomyopathy features are not currently being counted. This variant was identified in 0.0003% (FAF 95% CI; 2/113730) of European chromosomes by gnomAD v2.1.1 (PM2_Supporting; https://gnomad.broadinstitute.org). Following the ClinGen Sequence Variant Interpretation (SVI) working group recommendation for weight adjustment of the PM2 criterion due to concerns that rarity in the general population may not meet the relative odds of pathogenicity for moderate evidence, the PM2 criterion was downgraded to PM2_Supporting. This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be associated with HCM, but location in this region cannot be used to support pathogenicity for other phenotypes (Walsh 2017 PMID:27532257). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). Based on the majority of available evidence to date, this variant has been observed primarily in cis with MYH7 p.Asp955Asn and has rarely been reported in isolation; therefore, the clinical significance of the p.Asp545Asn variant alone is unclear. In summary, due to insufficient evidence, this variant meets criteria to be classified as uncertain significance for dilated cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Moderate, PP1, PM2_Supporting, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10587778/MONDO:0005021/002
Frequency
Consequence
NM_000257.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYH7 | NM_000257.4 | c.1633G>A | p.Asp545Asn | missense_variant | 16/40 | ENST00000355349.4 | |
MYH7 | NM_001407004.1 | c.1633G>A | p.Asp545Asn | missense_variant | 15/39 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYH7 | ENST00000355349.4 | c.1633G>A | p.Asp545Asn | missense_variant | 16/40 | 1 | NM_000257.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152136Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251434Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135886
GnomAD4 exome AF: 0.00000821 AC: 12AN: 1461892Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4AN XY: 727246
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152136Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74312
ClinVar
Submissions by phenotype
not provided Pathogenic:3Uncertain:2
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | AiLife Diagnostics, AiLife Diagnostics | Jun 30, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jun 15, 2023 | PP3, PM1, PM2_supporting - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Cardiovascular phenotype Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 14, 2022 | The p.D545N variant (also known as c.1633G>A), located in coding exon 14 of the MYH7 gene, results from a G to A substitution at nucleotide position 1633. The aspartic acid at codon 545 is replaced by asparagine, an amino acid with some highly similar properties. This variant along with MYH7 p.D955N in cis reportedly co-segregated with disease in families with dilated cardiomyopathy and left ventricular non-compaction (LVNC) (Hoedemaekers YM et al. Eur Heart J. 2007;28(22):2732-7; van den Berg MP et al. Eur J Heart Fail. 2010;12(12):1297-9). Both p.D545N and p.D955N were detected in another LVNC cohort; however, additional details were limited (Chang B. Mol Genet Metab. 2011 Feb;102(2):200-6). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic when in cis with MYH7 p.D955N; however, the clinical significance of the p.D545N variant alone is unclear. - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 24, 2023 | This missense variant replaces aspartic acid with asparagine at codon 545 of the MYH7 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in cis with p.Asp955Asn in multiple unrelated individuals affected with non-compaction cardiomyopathy (PMID: 17947214, 29447731, 30847666, 31771441). In one family, this variant was reported in 5 related individuals affected with non-compaction cardiomyopathy (PMID: 17947214); unaffected family members were not genotyped in this study. The double mutant allele has also been reported in four unrelated individuals affected with dilated cardiomyopathy (PMID: 23349452, 25332820, 35877578) and in two unrelated individuals affected with left ventricular noncompaction (PMID: 20965760, 27066506). This variant has been identified in 2/251434 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Hypertrophic cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 31, 2022 | ClinVar contains an entry for this variant (Variation ID: 264607). 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MYH7 protein function. This missense change has been observed in individual(s) with dilated cardiomyopathy and/or left ventricular non-compaction cardiomyopathy (PMID: 17947214, 20965760, 23349452). This variant is present in population databases (rs564101364, gnomAD 0.002%). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 545 of the MYH7 protein (p.Asp545Asn). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at