NM_000257.4(MYH7):c.788T>C (p.Ile263Thr) AND not provided

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: May 23, 2024
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:: RCV000158766.9

Allele description [Variation Report for NM_000257.4(MYH7):c.788T>C (p.Ile263Thr)]

NM_000257.4(MYH7):c.788T>C (p.Ile263Thr)

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.788T>C (p.Ile263Thr)

Other names:

p.I263T:ATA>ACA; NM_000257.3(MYH7):c.788T>C

HGVS:

NC_000014.9:g.23431426A>G
NG_007884.1:g.9236T>C
NM_000257.4:c.788T>CMANE SELECT
NP_000248.2:p.Ile263Thr
LRG_384t1:c.788T>C
LRG_384:g.9236T>C
NC_000014.8:g.23900635A>G
NM_000257.2:c.788T>C
NM_000257.3:c.788T>C
P12883:p.Ile263Thr
c.788T>C

Protein change:

I263T

Links:

UniProtKB: P12883#VAR_004571; dbSNP: rs397516269

NCBI 1000 Genomes Browser:

rs397516269

Molecular consequence:

NM_000257.4:c.788T>C - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Chain X, 40S RIBOSOMAL PROTEIN S23
Chain X, 40S RIBOSOMAL PROTEIN S23
gi|969813071|pdb|5FLX|X

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000208701	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (May 23, 2024)	germline	clinical testing	Citation Link,
SCV000280380	Stanford Center for Inherited Cardiovascular Disease, Stanford University	no assertion criteria provided	Likely pathogenic (Jun 23, 2015)	germline	clinical testing

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000208701

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(May 23, 2024)

germline

clinical testing

Citation Link,

SCV000280380

Stanford Center for Inherited Cardiovascular Disease, Stanford University

no assertion criteria provided

Likely pathogenic
(Jun 23, 2015)

germline

clinical testing

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	5	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Details of each submission

From GeneDx, SCV000208701.14

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 9829907, 12707239, 27737317, 23074333, 21425739, 16335287, 22429680, 24014347, 20624503, 22857948, 24093860, 9140839, 27532257, 27247418, 25937619, 29300372, 30297972, 31589614, 35653365, 28193612, 31513939, 33258288, 33586461, 36264615, 37652022, 15008060)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Stanford Center for Inherited Cardiovascular Disease, Stanford University, SCV000280380.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	5	not provided	not provided	clinical testing	not provided

Description

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. MYH7 p.Ile263Thr (c.788T>C) The variant has been seen in at least 5 unrelated cases. The database curated by the Seidman group notes that the variant was first reported in an individual with HCM by Tesson et al (1997) but was mistakenly referred to as p.Ile263Trp (http://genepath.med.harvard.edu/seidman//cg3/muts/MYH7_Ile263Thr.html). The same group did later report a family with two affected members with "I263T", presumably the same family and variant (Tesson et al 1998). Richard et al (2003) reported one HCM patient with this variant in their French cohort. Brito et al (2003, 2005) reported the variant in multiple family members of two unrelated Portugese families. Unfortunately only the abstracts are available so we could not confirm details. Millat et al (2010) observed the variant in one individual with HCM in their French cohort (appears to be distinct from the Richard et al cohort). In silico analysis with PolyPhen-2 predicts the variant to be probably damaging. The isoleucine at codon 263 is conserved across species, as are neighboring amino acids. Other variants have been reported in association with disease at this codon (p.Ile263Met, which we consider of uncertain significance, probably disease causing) and a nearby codon (p.Gly256Glu). In total the variant has not been seen in ~5700 published controls and publicly available population datasets. There is no variation at codon 263 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~5500 Caucasian and African American individuals (as of 1/16/2012). There is also no variation at this codon listed in dbSNP or 1000 genomes (as of 1/16/2012). The variant was not observed in the following published control samples: 100 (Tesson et al 1998), 100 (Richard et al 2003).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		5	not provided	not provided	not provided

Last Updated: Sep 16, 2024

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