rs267607235

chr4-127921639-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_001371596.2(MFSD8):c.1235C>T(p.Pro412Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000743 in 1,614,030 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P412G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: MFSD8 NM_001371596.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 8.73

Genes affected

MFSD8 (HGNC:28486): (major facilitator superfamily domain containing 8) This gene encodes a ubiquitous integral membrane protein that contains a transporter domain and a major facilitator superfamily (MFS) domain. Other members of the major facilitator superfamily transport small solutes through chemiosmotic ion gradients. The substrate transported by this protein is unknown. The protein likely localizes to lysosomal membranes. Mutations in this gene are correlated with a variant form of late infantile-onset neuronal ceroid lipofuscinoses (vLINCL). [provided by RefSeq, Oct 2008]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.977
• PP5: Variant 4-127921639-G-A is Pathogenic according to our data. Variant chr4-127921639-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1005.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-127921639-G-A is described in Lovd as [Likely_pathogenic]. Variant chr4-127921639-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MFSD8	NM_001371596.2	c.1235C>T	p.Pro412Leu	missense_variant	11/12	ENST00000641686.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MFSD8	ENST00000641686.2	c.1235C>T	p.Pro412Leu	missense_variant	11/12		NM_001371596.2	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152164 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251370 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135854

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000752 AC: 11 AN: 1461866 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 727232

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000629

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152164 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74332

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neuronal ceroid lipofuscinosis 7 Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Mar 12, 2023	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects MFSD8 function (PMID: 22668694). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MFSD8 protein function. ClinVar contains an entry for this variant (Variation ID: 1005). This missense change has been observed in individual(s) with clinical features of neuronal ceroid lipofuscinosis (PMID: 19277732; Invitae). 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 (rs267607235, gnomAD 0.006%). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 412 of the MFSD8 protein (p.Pro412Leu). -
Likely pathogenic, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 14, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jun 09, 2020	This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2009	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jun 11, 2020	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from proline to leucine (exon 12). (N) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (5 heterozygotes, 0 homozygotes). (P) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (P) 0600 - Variant is located in an annotated domain or motif, (the junction btw transmembrane domain 10 and 9; PMID:19277732). (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0802 - Moderate previous evidence of pathogenicity. This variant has been reported as homozygous and compound heterozygous in two families with neuronal ceroid lipofuscinosis and cone rod dystrophy, respectively (LOVD, ClinVar, PMID: 19277732, PMID: 31006324). (P) 0901 - Strong evidence for segregation with disease in two families (PMID: 19277732, PMID: 31006324). (P) 1002 - Moderate functional evidence supporting abnormal protein function. Assays demonstrated that mutant protein was more readily cleaved and degraded (PMID:22668694). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -

Neuronal ceroid lipofuscinosis 7;C4015371:Macular dystrophy with central cone involvement Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 09, 2022

- -

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 11, 2016

The p.P412L variant (also known as c.1235C>T), located in coding exon 11 of the MFSD8 gene, results from a C to T substitution at nucleotide position 1235. The proline at codon 412 is replaced by leucine, an amino acid with similar properties. A study analyzing the functional proteolytic cleavage activity of this gene in COS-7 cells found that this variant resulted in increased proteolytic cleavage of the CLN7 protein in lysosomes presumably resulting in a non-functional protein (Steenhuis et al. Biochim Biophys Acta. 2012;1822 (10):1617-28). In another study, the p.P412L variant (referred to as c.1398C>T) was identified in a homozygous state in a consanguineous Saudi Arabian family with three affected children. The index case was a 10-year-old boy who developed progressive blindness, focal seizures with secondary generalized tonic clonic convulsions, and progressive decline in cognitive function in association with the Turkish variant of late-infantile Neuronal Ceroid Lipofuscinosis, characterized by a later age of onset and a more severe seizure phenotype (Aldahmesh et al. Neurogenetics. 2009;10:307-311). This variant was previously reported in the SNPDatabase as rs267607235. This variant was not reported in population-based cohorts in the following databases: NHLBI Exome Sequencing Project (ESP) and 1000 Genomes Project. In the ESP, this variant was not observed in 6,503 samples (13,006 alleles) with coverage at this position.This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Jun 28, 2023

- -

Neuronal ceroid lipofuscinosis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Mar 01, 2022

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.39
Cadd	Pathogenic	32
Dann	Uncertain	1.0
DEOGEN2	Benign	0.32	T;T;.;.;.;.;.;.;.;.
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.43	D
MutationAssessor	Pathogenic	3.1	M;M;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.60	T
Polyphen		1.0	D;D;.;.;.;.;.;.;.;.
Vest4		0.97
MutPred		0.83		Loss of helix (P = 0.2271);Loss of helix (P = 0.2271);.;.;.;.;.;.;.;Loss of helix (P = 0.2271);
MVP		0.88
MPC		0.50
ClinPred		0.99	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.49
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs267607235; hg19: chr4-128842794;