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NM_000257.4(MYH7):c.698C>T (p.Ala233Val) AND not provided

Germline classification:
Uncertain significance (2 submissions)
Last evaluated:
Oct 14, 2015
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV000766410.3

Allele description [Variation Report for NM_000257.4(MYH7):c.698C>T (p.Ala233Val)]

NM_000257.4(MYH7):c.698C>T (p.Ala233Val)

Gene:
MYH7:myosin heavy chain 7 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
14q11.2
Genomic location:
Preferred name:
NM_000257.4(MYH7):c.698C>T (p.Ala233Val)
HGVS:
  • NC_000014.9:g.23431619G>A
  • NG_007884.1:g.9043C>T
  • NM_000257.4:c.698C>TMANE SELECT
  • NP_000248.2:p.Ala233Val
  • LRG_384t1:c.698C>T
  • LRG_384:g.9043C>T
  • NC_000014.8:g.23900828G>A
  • NM_000257.2:c.698C>T
Protein change:
A233V
Links:
dbSNP: rs727504362
NCBI 1000 Genomes Browser:
rs727504362
Molecular consequence:
  • NM_000257.4:c.698C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:
none provided
Identifiers:
MedGen: C3661900

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000208813GeneDx
criteria provided, single submitter

(GeneDx Variant Classification (06012015))		Uncertain significance
(Oct 14, 2015) 		germlineclinical testing

Citation Link,

SCV000924870Stanford Center for Inherited Cardiovascular Disease, Stanford University
no assertion criteria provided
Uncertain significance
(Oct 11, 2017) 		germlineprovider interpretation

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedprovider interpretation

Details of each submission

From GeneDx, SCV000208813.12

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

Although the A233V variant has not been reported as a pathogenic variant or a benign variant, to our knowledge, it has previously been identified in one other individual who underwent genetic testing for cardiomyopathy . This variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Missense variants in nearby residues (A223T, L227V, N232S, T235N, V236I, D239N, R243C, R243H) including a different missense variant at the same residue (A233S) have been reported in HGMD in association with cardiomyopathy (Stenson et al., 2014), supporting the functional importance of this residue and region of the protein. This substitution occurs at a position that is conserved across species. However, the A233V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Furthermore, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Stanford Center for Inherited Cardiovascular Disease, Stanford University, SCV000924870.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedprovider interpretationnot provided

Description

Found in a pediatric patient with LVNC who had a Comprehensive Cardiomyopathy Panel with the GeneDx laboratory. The test included sequencing of 76 genes and additional deletion/duplication analysis of 60 of those genes (nuclear genes) associated with various forms of cardiomyopathy: ABCC9 , ACTC (ACTC1), ACTN2, ANKRD1, BAG3 , BRAF, CAV3, CRYAB , CSRP3, DES, DMD, DSC2, DSG2, DSP, DTNA, EMD, FKTN, GATAD1, GLA, HRAS, ILK, JPH2, JUP, KRAS, LAMA4, LAMP2, LDB3 (ZASP), LMNA, MAP2K1, MAP2K2, MTND1, MTND5, MTND6, MTTD, MTTG, MTTH, MTTI, MTTK, MTTL1, MTTL2, MTTM, MTTQ, MTTS1, MTTS2, MYBPC3, MYH7, MYL2, MYL3, MYLK2, MYOZ2, MYPN, NEBL , NEXN, NRAS, PDLIM3, PKP2, PLN, PRKAG2, PTPN11, RAF1, RBM20, RYR2, SCN5A, SGCD, SOS1, TAZ, TCAP, TMEM43, TMPO, TNNC1, TNNI3, TNNT2, TPM1, TTN, TTR, VCL. Results show that 2 variants were detected: • p.Glu561_Glu562del (c.1677_1682delGGAGGA) in the NEXN gene - which we consider likely to be benign because it is 10x more frequent in patients with African ancestry such as this patient • p.Ala233Val (c.698C>T) in the MYH7 gene p.Ala233Val (c.698C>T) in exon 8 of the MYH7 gene Chromosome location 14:23900828 G / A Based on the data reviewed below we consider this to be a Variant of Uncertain Significance, but still consider it a good candidate to be disease-causing. More data is required to understand its clinical significance. This variant has not been reported in the literature in association with disease, to the best of our knowledge. Girolami et al. (2006) reported a different variant at the same residue, Ala233Ser, in an Italian patient with hypertrophic cardiomyopathy. This is a conservative amino acid change, resulting in the replacement of a nonpolar Alanine with a nonpolar Valine. Alanine at this location is absolutely conserved across ~100 vertebrate species for which we have data. The adjacent residues are also highly conserved. Missense variants at nearby residues (+/- 10 amino acids), including a different missense variant at the same residue (Ala233Ser), have been reported in ClinVar as Likely Pathogenic or Pathogenic: Arg243His, Asp239Asn, Arg237Trp, Ala233Ser, Ala226Val, Ala226Thr. This supports the functional importance of this region of the protein. The variant is in the head of myosin, which is enriched for pathogenic variation. Specifically, it is in the ATP-binding domain. In silico prediction models are not in agreement regarding this variant. Analysis with Mutation Taster considers it “disease causing” while PolyPhen-2 predicts that it is "benign." There is no variation at this residue reported in the gnomAD database, which includes variant calls on ~140,000 individuals of European, African, Latino, South Asian, Ashkenazi, and East Asian descent. There is good coverage at this site. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. The curators made an effort to exclude individuals with severe pediatric diseases.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024