NM_000257.4(MYH7):c.4835T>C (p.Leu1612Pro) AND Hypertrophic cardiomyopathy

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Mar 23, 2023
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:: RCV000459843.8

Allele description [Variation Report for NM_000257.4(MYH7):c.4835T>C (p.Leu1612Pro)]

NM_000257.4(MYH7):c.4835T>C (p.Leu1612Pro)

Genes:

LOC126861897:BRD4-independent group 4 enhancer GRCh37_chr14:23884455-23885654 [Gene]
MYH7:myosin heavy chain 7 [Gene - OMIM - HGNC]
MHRT:myosin heavy chain associated RNA transcript [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

14q11.2

Genomic location:

Preferred name:

NM_000257.4(MYH7):c.4835T>C (p.Leu1612Pro)

Other names:

NM_000257.4(MYH7):c.4835T>C

HGVS:

NC_000014.9:g.23416122A>G
NG_007884.1:g.24540T>C
NM_000257.4:c.4835T>CMANE SELECT
NP_000248.2:p.Leu1612Pro
LRG_384t1:c.4835T>C
LRG_384:g.24540T>C
LRG_384p1:p.Leu1612Pro
NC_000014.8:g.23885331A>G
NM_000257.2:c.4835T>C
NM_000257.3:c.4835T>C
NR_126491.1:n.383A>G

Protein change:

L1612P

Links:

dbSNP: rs587779392

NCBI 1000 Genomes Browser:

rs587779392

Molecular consequence:

NM_000257.4:c.4835T>C - missense variant - [Sequence Ontology: SO:0001583]
NR_126491.1:n.383A>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Hypertrophic cardiomyopathy
Synonyms:: HYPERTROPHIC MYOCARDIOPATHY
Identifiers:: MONDO: MONDO:0005045; MeSH: D002312; MedGen: C0007194; Human Phenotype Ontology: HP:0001639

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Mus musculus cDNA clone IMAGE:9054145
Mus musculus cDNA clone IMAGE:9054145
gi|219518721|gb|BC145579.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000546201	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Mar 23, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 24664454, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000546201

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Mar 23, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Citations

PubMed

Novel mutations widen the phenotypic spectrum of slow skeletal/β-cardiac myosin (MYH7) distal myopathy.

Lamont PJ, Wallefeld W, Hilton-Jones D, Udd B, Argov Z, Barboi AC, Bonneman C, Boycott KM, Bushby K, Connolly AM, Davies N, Beggs AH, Cox GF, Dastgir J, DeChene ET, Gooding R, Jungbluth H, Muelas N, Palmio J, Penttilä S, Schmedding E, Suominen T, et al.

Hum Mutat. 2014 Jul;35(7):868-79. doi: 10.1002/humu.22553. Epub 2014 May 21.

PubMed [citation]

PMID:: 24664454
PMCID:: PMC4112555

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Invitae, SCV000546201.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This variant is not present in population databases (gnomAD no frequency). 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. 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. ClinVar contains an entry for this variant (Variation ID: 143213). This missense change has been observed in individuals with clinical features of autosomal dominant MYH7-related conditions (PMID: 24664454; Invitae). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 1612 of the MYH7 protein (p.Leu1612Pro).

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

Last Updated: Mar 30, 2024

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