chr6-35505751-C-A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_003322.6(TULP1):c.1102G>T(p.Gly368Trp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,882 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. G368R) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

TULP1
NM_003322.6 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 7.90

Publications

10 publications found

Variant links:

Genes affected

TULP1 (HGNC:12423): (TUB like protein 1) This gene encodes a member of the tubby-like gene family (TULPs). Members of this family have been identified in plants, vertebrates, and invertebrates. TULP proteins share a conserved C-terminal region of approximately 200 amino acid residues. The protein encoded by this gene is thought to play a role in the physiology of photoreceptors. Mutations in this gene are associated with recessive juvenile retinitis pigmentosa and Leber congenital amaurosis-15. [provided by RefSeq, Nov 2016]

TULP1 Gene-Disease associations (from GenCC):

retinitis pigmentosa 14
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
Leber congenital amaurosis 15
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
Leber congenital amaurosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
retinitis pigmentosa
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

TULP1 links:

ENSG00000228559 (HGNC:58100):

ENSG00000228559 links:

LOC124901309 (HGNC:):

LOC124901309 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 17 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr6-35505750-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3678382.Status of the report is criteria_provided_single_submitter, 1 stars.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 30 curated pathogenic missense variants (we use a threshold of 10). The gene has 7 curated benign missense variants. Gene score misZ: 0.64726 (below the threshold of 3.09). Trascript score misZ: -0.4024 (below the threshold of 3.09). GenCC associations: The gene is linked to retinitis pigmentosa, retinitis pigmentosa 14, Leber congenital amaurosis 15, Leber congenital amaurosis.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.993

PP5

Variant 6-35505751-C-A is Pathogenic according to our data. Variant chr6-35505751-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 30262.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TULP1	NM_003322.6 link	c.1102G>T	p.Gly368Trp	missense_variant	Exon 11 of 15	ENST00000229771.11	NP_003313.3	O00294-1Q0QD38
TULP1	NM_001289395.2 link	c.943G>T	p.Gly315Trp	missense_variant	Exon 10 of 14		NP_001276324.1	O00294-2F1T0I9
LOC124901309	XR_007059561.1 link	n.76-2476C>A		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TULP1	ENST00000229771.11 link	c.1102G>T	p.Gly368Trp	missense_variant	Exon 11 of 15	1	NM_003322.6	ENSP00000229771.6		O00294-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251300

AF XY:

0.00000736

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461882

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727238

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1112010

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Leber congenital amaurosis 15

Pathogenic:2

Apr 01, 2004

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Laboratory of Genetics in Ophthalmology, Institut Imagine

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Leber congenital amaurosis

Pathogenic:1

Apr 11, 2024

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: TULP1 c.1102G>T (p.Gly368Trp) results in a non-conservative amino acid change located in the Tubby, C-terminal domain (IPR000007) 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 4e-06 in 251300 control chromosomes (gnomAD). c.1102G>T has been reported in the literature in multiple individuals affected with Leber Congenital Amaurosis (Hanein_2004, Abbasi_2008, Wang_2013, Jacobson_2014, Karali_2022). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 18432314, 15024725, 25074776, 36460718, 23847139). ClinVar contains an entry for this variant (Variation ID: 30262). Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:1

Mar 12, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ClinVar contains an entry for this variant (Variation ID: 30262). This sequence change replaces glycine, which is neutral and non-polar, with tryptophan, which is neutral and slightly polar, at codon 368 of the TULP1 protein (p.Gly368Trp). This variant is present in population databases (rs387906837, gnomAD 0.0009%). This missense change has been observed in individual(s) with Leber congenital amaurosis and/or retinitis pigmentosa (PMID: 15024725, 25074776; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. 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 TULP1 protein function. This variant disrupts the p.Gly368 amino acid residue in TULP1. Other variant(s) that disrupt this residue have been observed in individuals with TULP1-related conditions (PMID: 31736247), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Retinal dystrophy

Pathogenic:1

Jan 01, 2023

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Retinitis pigmentosa 14;C3151206:Leber congenital amaurosis 15

Pathogenic:1

Apr 16, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.68

BayesDel_noAF

Pathogenic

0.74

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.96

.;D;D

Eigen

Pathogenic

0.92

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

D;D;D

M_CAP

Pathogenic

0.84

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.9

.;H;.

PhyloP100

7.9

PrimateAI

Uncertain

0.76

PROVEAN

Pathogenic

-7.9

D;D;.

REVEL

Pathogenic

0.97

Sift

Pathogenic

0.0

D;D;.

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;D;.

Vest4

0.97

MutPred

0.95

.;Loss of disorder (P = 0.0138);.;

MVP

0.93

MPC

1.0

ClinPred

1.0

GERP RS

4.4

Varity_R

0.98

gMVP

0.90

Mutation Taster

=6/94

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over