NM_170707.4(LMNA):c.1517A>C (p.His506Pro) AND not provided

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Apr 1, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000235371.16

Allele description [Variation Report for NM_170707.4(LMNA):c.1517A>C (p.His506Pro)]

NM_170707.4(LMNA):c.1517A>C (p.His506Pro)

Gene:

LMNA:lamin A/C [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1q22

Genomic location:

Preferred name:

NM_170707.4(LMNA):c.1517A>C (p.His506Pro)

HGVS:

NC_000001.11:g.156137141A>C
NG_008692.2:g.59569A>C
NM_001257374.3:c.1181A>C
NM_001282624.2:c.1274A>C
NM_001282625.2:c.1517A>C
NM_001282626.2:c.1517A>C
NM_005572.4:c.1517A>C
NM_170707.4:c.1517A>CMANE SELECT
NM_170708.4:c.1517A>C
NP_001244303.1:p.His394Pro
NP_001269553.1:p.His425Pro
NP_001269554.1:p.His506Pro
NP_001269555.1:p.His506Pro
NP_005563.1:p.His506Pro
NP_005563.1:p.His506Pro
NP_733821.1:p.His506Pro
NP_733822.1:p.His506Pro
LRG_254t1:c.1517A>C
LRG_254t2:c.1517A>C
LRG_254:g.59569A>C
LRG_254p1:p.His506Pro
NC_000001.10:g.156106932A>C
NM_005572.3:c.1517A>C
NM_170707.2:c.1517A>C
NM_170707.3:c.1517A>C
p.(His506Pro)

Protein change:

H394P

Links:

dbSNP: rs878855233

NCBI 1000 Genomes Browser:

rs878855233

Molecular consequence:

NM_001257374.3:c.1181A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001282624.2:c.1274A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001282625.2:c.1517A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001282626.2:c.1517A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_005572.4:c.1517A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_170707.4:c.1517A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_170708.4:c.1517A>C - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

Recent activity

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Rattus norvegicus myosin heavy chain 3 (Myh3), mRNA
Rattus norvegicus myosin heavy chain 3 (Myh3), mRNA
gi|6981233|ref|NM_012604.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000292723	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Uncertain significance (Jun 4, 2015)	germline	clinical testing	Citation Link,
SCV004124992	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Uncertain significance (Apr 1, 2023)	germline	clinical testing	Citation Link,
SCV004848122	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Dec 20, 2021)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 28531892, 27813223, 29255176, 29693488, 30326651, 32880476, 31744510, 32041611, 31383942, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000292723

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Uncertain significance
(Jun 4, 2015)

germline

clinical testing

Citation Link,

SCV004124992

CeGaT Center for Human Genetics Tuebingen

criteria provided, single submitter

(CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)

Uncertain significance
(Apr 1, 2023)

germline

clinical testing

Citation Link,

SCV004848122

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Dec 20, 2021)

germline

clinical testing

PubMed (10)
[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	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Emery-Dreifuss Muscular Dystrophy-Associated Mutant Forms of Lamin A Recruit the Stress Responsive Protein Ankrd2 into the Nucleus, Affecting the Cellular Response to Oxidative Stress.

Angori S, Capanni C, Faulkner G, Bean C, Boriani G, Lattanzi G, Cenni V.

Cell Physiol Biochem. 2017;42(1):169-184. doi: 10.1159/000477309. Epub 2017 May 25.

PubMed [citation]

PMID:: 28531892

Truncating titin mutations are associated with a mild and treatable form of dilated cardiomyopathy.

Jansweijer JA, Nieuwhof K, Russo F, Hoorntje ET, Jongbloed JD, Lekanne Deprez RH, Postma AV, Bronk M, van Rijsingen IA, de Haij S, Biagini E, van Haelst PL, van Wijngaarden J, van den Berg MP, Wilde AA, Mannens MM, de Boer RA, van Spaendonck-Zwarts KY, van Tintelen JP, Pinto YM.

Eur J Heart Fail. 2017 Apr;19(4):512-521. doi: 10.1002/ejhf.673. Epub 2016 Nov 3.

PubMed [citation]

PMID:: 27813223

See all PubMed Citations (10)

Details of each submission

From GeneDx, SCV000292723.10

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

Description

The H506P variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The H506P variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The H506P variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in most mammals, however Proline is the wild type residue at this position in platypus and Alanine is present at this position in alpaca. Missense mutations in this residue (H506D) and nearby residues (W498R, W498C, L512P) have been reported in the Human Gene Mutation Database in association with metabolic laminopathy, muscular dystrophy and myopathy (Stenson et al., 2014), supporting the functional importance of this region of the protein. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.

#	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 CeGaT Center for Human Genetics Tuebingen, SCV004124992.10

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

Description

LMNA: PM1, PM2:Supporting, PS4:Supporting

#	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		1	not provided	not provided	not provided

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV004848122.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

Description

The p.His506Pro variant in LMNA has been reported in 4 individuals with DCM, 1 individual with HCM, 1 individual with cardiac conduction defects, 1 individual with cystic kidney disease, and 1 individual with familial partial lipodystrophy (Angori 2017 PMID: 28531892, Jansweijer 2017 PMID: 27813223, Robyns 2017 PMID: 29255176, Ditaranto 2019 PMID: 31744510, Dron 2020 PMID: 32041611, Park 2020 PMID: 31383942, Verdonschot 2020 PMID: 32880476, Visser 2016). It has also been identified in 0.005% (7/127728) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In vitro functional studies provide some evidence that this variant impacts protein function (Angori 2017 PMID: 28531892, Bernasconi 2018 PMID: 29693488, Mattioli 2018 PMID: 30326651); however, these types of assays may not accurately represent biological function. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PS3_Supporting.

#	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: Oct 20, 2024

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