NM_006343.3(MERTK):c.2530C>T (p.Arg844Cys) AND not provided

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Dec 1, 2022
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:: RCV001389819.18

Allele description [Variation Report for NM_006343.3(MERTK):c.2530C>T (p.Arg844Cys)]

NM_006343.3(MERTK):c.2530C>T (p.Arg844Cys)

Gene:

MERTK:MER proto-oncogene, tyrosine kinase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2q13

Genomic location:

Preferred name:

NM_006343.3(MERTK):c.2530C>T (p.Arg844Cys)

HGVS:

NC_000002.12:g.112028394C>T
NG_011607.1:g.134781C>T
NM_006343.3:c.2530C>TMANE SELECT
NP_006334.2:p.Arg844Cys
NC_000002.11:g.112785971C>T

Protein change:

R844C

Links:

dbSNP: rs746291728

NCBI 1000 Genomes Browser:

rs746291728

Molecular consequence:

NM_006343.3:c.2530C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

Recent activity

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PREDICTED: Homo sapiens transmembrane protein 128 (TMEM128), transcript variant ...
PREDICTED: Homo sapiens transmembrane protein 128 (TMEM128), transcript variant X1, mRNA
gi|2217352467|ref|XM_005248034.4|

Nucleotide
PREDICTED: Gallus gallus vav 3 guanine nucleotide exchange factor (VAV3), transc...
PREDICTED: Gallus gallus vav 3 guanine nucleotide exchange factor (VAV3), transcript variant X6, mRNA
gi|2201692609|ref|XM_046944196.1|

Nucleotide
lncRNA:CR43266 long non-coding RNA:CR43266 [Drosophila melanogaster]
lncRNA:CR43266 long non-coding RNA:CR43266 [Drosophila melanogaster]
Gene ID:54520460

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001591304	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 24, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 15111602, 28462455, 28492532
SCV002822682	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (Dec 1, 2022)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001591304

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 24, 2022)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV002822682

CeGaT Center for Human Genetics Tuebingen

criteria provided, single submitter

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

Pathogenic
(Dec 1, 2022)

germline

clinical testing

Citation Link

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

MERTK arginine-844-cysteine in a patient with severe rod-cone dystrophy: loss of mutant protein function in transfected cells.

McHenry CL, Liu Y, Feng W, Nair AR, Feathers KL, Ding X, Gal A, Vollrath D, Sieving PA, Thompson DA.

Invest Ophthalmol Vis Sci. 2004 May;45(5):1456-63.

PubMed [citation]

PMID:: 15111602

A novel MERTK mutation causing retinitis pigmentosa.

Al-Khersan H, Shah KP, Jung SC, Rodriguez A, Madduri RK, Grassi MA.

Graefes Arch Clin Exp Ophthalmol. 2017 Aug;255(8):1613-1619. doi: 10.1007/s00417-017-3679-9. Epub 2017 May 1.

PubMed [citation]

PMID:: 28462455
PMCID:: PMC5542860

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001591304.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects MERTK function (PMID: 15111602). 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 MERTK protein function. ClinVar contains an entry for this variant (Variation ID: 801738). This missense change has been observed in individual(s) with autosomal recessive inherited retinal dystrophy (PMID: 15111602, 28462455). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs746291728, gnomAD 0.002%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 844 of the MERTK protein (p.Arg844Cys).

#	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

From CeGaT Center for Human Genetics Tuebingen, SCV002822682.13

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

Description

MERTK: PM3:Strong, PM2, PM5, PP4, PS3: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

Last Updated: Oct 13, 2024

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