NM_001371596.2(MFSD8):c.1235C>T (p.Pro412Leu) AND Neuronal ceroid lipofuscinosis

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Mar 1, 2022
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:: RCV002222334.9

Allele description [Variation Report for NM_001371596.2(MFSD8):c.1235C>T (p.Pro412Leu)]

NM_001371596.2(MFSD8):c.1235C>T (p.Pro412Leu)

Gene:

MFSD8:major facilitator superfamily domain containing 8 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

4q28.2

Genomic location:

Preferred name:

NM_001371596.2(MFSD8):c.1235C>T (p.Pro412Leu)

HGVS:

NC_000004.12:g.127921639G>A
NG_008657.1:g.49346C>T
NM_001363520.3:c.1034C>T
NM_001363521.3:c.920C>T
NM_001371590.2:c.1100C>T
NM_001371591.2:c.1235C>T
NM_001371592.2:c.1241C>T
NM_001371593.2:c.1121C>T
NM_001371594.2:c.1088C>T
NM_001371595.1:c.953C>T
NM_001371596.2:c.1235C>TMANE SELECT
NM_001410765.1:c.785C>T
NM_001410766.1:c.*120C>T
NM_152778.4:c.1235C>T
NP_001350449.1:p.Pro345Leu
NP_001350449.1:p.Pro345Leu
NP_001350450.1:p.Pro307Leu
NP_001350450.1:p.Pro307Leu
NP_001358519.1:p.Pro367Leu
NP_001358519.1:p.Pro367Leu
NP_001358520.1:p.Pro412Leu
NP_001358520.1:p.Pro412Leu
NP_001358521.1:p.Pro414Leu
NP_001358521.1:p.Pro414Leu
NP_001358522.1:p.Pro374Leu
NP_001358522.1:p.Pro374Leu
NP_001358523.1:p.Pro363Leu
NP_001358523.1:p.Pro363Leu
NP_001358524.1:p.Pro318Leu
NP_001358525.1:p.Pro412Leu
NP_001397694.1:p.Pro262Leu
NP_689991.1:p.Pro412Leu
LRG_833t1:c.1235C>T
LRG_833t2:c.1235C>T
LRG_833:g.49346C>T
LRG_833p1:p.Pro412Leu
LRG_833p2:p.Pro412Leu
NC_000004.11:g.128842794G>A
NM_001363520.2:c.1034C>T
NM_001363521.2:c.920C>T
NM_001371590.1:c.1100C>T
NM_001371591.1:c.1235C>T
NM_001371592.1:c.1241C>T
NM_001371593.1:c.1121C>T
NM_001371594.1:c.1088C>T
NM_152778.2:c.1235C>T
NM_152778.3:c.1235C>T
Q8NHS3:p.Pro412Leu

Protein change:

P262L; PRO412LEU

Links:

UniProtKB: Q8NHS3#VAR_072674; OMIM: 611124.0005; dbSNP: rs267607235

NCBI 1000 Genomes Browser:

rs267607235

Molecular consequence:

NM_001363520.3:c.1034C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001363521.3:c.920C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001371590.2:c.1100C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001371591.2:c.1235C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001371592.2:c.1241C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001371593.2:c.1121C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001371594.2:c.1088C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001371595.1:c.953C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001371596.2:c.1235C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001410765.1:c.785C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_152778.4:c.1235C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Neuronal ceroid lipofuscinosis
Synonyms:: Ceroid storage disease
Identifiers:: MONDO: MONDO:0016295; MedGen: C0027877; Orphanet: 79263; OMIM: PS256730

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002500268	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Mar 1, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 26075876, 31006324, 19277732, 22668694 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002500268

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Mar 1, 2022)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link

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

Lysoplex: An efficient toolkit to detect DNA sequence variations in the autophagy-lysosomal pathway.

Di Fruscio G, Schulz A, De Cegli R, Savarese M, Mutarelli M, Parenti G, Banfi S, Braulke T, Nigro V, Ballabio A.

Autophagy. 2015;11(6):928-38. doi: 10.1080/15548627.2015.1043077.

PubMed [citation]

PMID:: 26075876
PMCID:: PMC4502703

MFSD8 gene mutations; evidence for phenotypic heterogeneity.

Zare-Abdollahi D, Bushehri A, Alavi A, Dehghani A, Mousavi-Mirkala M, Effati J, Miratashi SAM, Dehani M, Jamali P, Khorram Khorshid HR.

Ophthalmic Genet. 2019 Apr;40(2):141-145. doi: 10.1080/13816810.2019.1592200. Epub 2019 Apr 22.

PubMed [citation]

PMID:: 31006324

See all PubMed Citations (4)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002500268.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

Variant summary: MFSD8 c.1235C>T (p.Pro412Leu) results in a non-conservative amino acid change located in the Major facilitator superfamily domain (IPR020846) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251370 control chromosomes (gnomAD). c.1235C>T has been reported in the literature in multiple individuals/families affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease) and cone-rod dystrophy (e.g. Aldahmesh_2009, Di Fruscio_2015, Zare-Abdollahi_2019). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant enhanced its proteolytic cleavage in lysosomes (Steenhuis_2012). Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

#	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: Nov 24, 2024

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