rs397516097
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2_SupportingPM1PP3PS4_Supporting
This summary comes from the ClinGen Evidence Repository: The c.1273G>A (p.Gly425Arg) variant in MYH7 has been identified in at least 3 individuals with HCM, the majority of whom are of Chinese ancestry (PS4_Supporting; Song 2005 PMID:15563892; Wang 2009 PMID:19586842; Homburger 2016 PMID:27247418; Mak 2018 PMID:29497013). This variant segregated with disease in 2 relatives with HCM from 1 family (Wang 2009 PMID:19586842); however this data is currently insufficient to apply PP1. This variant was absent from large population studies (PM2_Supporting; http://gnomad.broadinstitute.org, v2.1.1). 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 disease-associated (PM1; Walsh 2017 PMID:27532257). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, due to insufficient evidence, this variant meets criteria to be classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Supporting; PM2_Supporting; PM1; PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA010465/MONDO:0005045/002
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 | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MYH7 | NM_000257.4 | c.1273G>A | p.Gly425Arg | missense_variant | 14/40 | ENST00000355349.4 | NP_000248.2 | |
MYH7 | NM_001407004.1 | c.1273G>A | p.Gly425Arg | missense_variant | 13/39 | NP_001393933.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MYH7 | ENST00000355349.4 | c.1273G>A | p.Gly425Arg | missense_variant | 14/40 | 1 | NM_000257.4 | ENSP00000347507.3 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 33
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Hypertrophic cardiomyopathy Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Mar 14, 2022 | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant is found within a region of MYH7 between codons 181 and 937 that contains the majority of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 42834). This missense change has been observed in individuals with clinical features of MYH7-related conditions (PMID: 15563892, 19586842, 27247418, 29497013, 32931854; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 425 of the MYH7 protein (p.Gly425Arg). - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Feb 05, 2019 | proposed classification - variant undergoing re-assessment, contact laboratory - |
Hypertrophic cardiomyopathy 1 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Sep 02, 2022 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established; however, missense variants have been proposed to act in a dominant negative manner (PMID: 24714796). (I) 0108 - This gene is associated with both recessive and dominant disease. Pathogenic variants in this gene are usually heterozygous; however, a recessive inheritance pattern has been observed in severe cases (OMIM). (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID: 29300372). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to arginine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants. This variant is found within the head region, which is enriched with pathogenic missense variants (PMID: 29300372). (SP) 0710 - Another missense variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. The p.(Gly425Ala) variant has been classified once as a VUS by a clinical diagnostic laboratory (ClinVar). (I) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported in four individuals with HCM (ClinVar, PMIDs: 15563892, 29497013, 27247418). It should also be noted that although this variant was classified as a VUS by two clinical diagnostic laboratories; evaluation of the variant was performed in 2015 (ClinVar). (SP) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
not specified Uncertain:1
Uncertain significance, flagged submission | clinical testing | Stanford Center for Inherited Cardiovascular Disease, Stanford University | Feb 24, 2015 | 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.Gly425Arg (c.1273G>A) in the MYH7 gene. The patient's genetic test results were first reviewed in 2007. They were re-reviewed 1/31/12, 5/15/13, and 17 March 2015. This variant has been reported in at least two cases of HCM (not including our patient) with moderate segregation data and seen in an additional case with a family history of HCM. Song et al (2005) reported the variant in one case of HCM with no segregation data provided. The same group reported a family with four individuals with p.Gly425Arg (Wang et al 2009). Unfortunately that publication is in Chinese, so it is difficult to assess whether it is the same family. We did have a member of our team who reads Chinese review the paper and found that the variant was seen in three family members with HCM and one obligate carrier. There is an assertion in ClinVar as likely pathogenic, from LMM (SCV000059363). They do not note any additional case data and they have not reviewed it since 2010. I contacted them and they shared that they have seen it in one unaffected individual with a family history of HCM, they have not tested any affected individuals. GeneDx also has an assertion in ClinVar, as pathogenic. Other variants at nearby codons have been reported in association with HCM: p.Ala428Val, (Richard et al., 2003; Van Driest et al., 2004), p.Ala430Glu (Morner et al., 2003), and p. Met435Thr (Sawyer et al., 2003). This is a non-conservative amino acid change with a non-polar neutral Glycine replaced with a polar positive Arginine. Glycine at codon 425 is completely conserved in MYH7 across species. In silico analysis (PolyPhen 2) predicts the variant to be probably damaging. In ClinVar LMM notes that their in-house computational tool predicts it to be pathogenic (and is correct 94% of the time) (Jordan et al 2011). The variant was not observed in a total of ~64,120 published and publicly available general population samples, with ~4420 of those matching this patient's ancestry (and the ancestry of the published cases). Specifically, this variant was not observed in 120 published Chinese control individuals (Song et al 2005). This is likely the same 120 control individuals reported by Wang et al (2009). The variant is not reported in dbSNP or 1000 genomes (as of 5/15/13.) There is no variation at codon 425 listed in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of January 21st, 2015). This includes ~4300 Easy Asian individuals. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 04, 2023 | In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at significant frequency in large population cohorts (gnomAD); Identified in patients with cardiomyopathy referred for genetic testing at GeneDx and in published literature (Song et al., 2005; Wang et al., 2009; Homburger et al., 2016; Mak et al., 2018); This variant is associated with the following publications: (PMID: 27247418, 19586842, 15563892, 32931854, 29497013, 27532257, 29300372, 34949102, 31856055) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at