chr6-35500100-A-T

Variant names:

• chr6-35500100-A-T
• rs121909075
• NM_003322.6:c.1376T>A

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PP2 PP3_Strong PP5_Very_Strong

The NM_003322.6(TULP1):​c.1376T>A​(p.Ile459Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,876 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. I459T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: TULP1 NM_003322.6 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.47
• Publications: 22 publications found

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

ENSG00000228559 (HGNC:58100):

LOC124901309 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• 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, 0.978
• PP5: Variant 6-35500100-A-T is Pathogenic according to our data. Variant chr6-35500100-A-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 7359.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	c.1376T>A	p.Ile459Lys	missense_variant	Exon 14 of 15	ENST00000229771.11	NP_003313.3
TULP1	NM_001289395.2	c.1217T>A	p.Ile406Lys	missense_variant	Exon 13 of 14		NP_001276324.1
LOC124901309	XR_007059561.1	n.75+1893A>T		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TULP1	ENST00000229771.11	c.1376T>A	p.Ile459Lys	missense_variant	Exon 14 of 15	1	NM_003322.6	ENSP00000229771.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461876 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727240

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1112010

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Retinitis pigmentosa 14 Pathogenic:1

Feb 01, 1998

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Leber congenital amaurosis Pathogenic:1

Mar 25, 2025

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: TULP1 c.1376T>A (p.Ile459Lys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251456 control chromosomes (gnomAD). c.1376T>A has been reported in the literature in individuals affected with retinitis pigmentosa or retinal disease (Hagstrom_1998, Holtan_2020). At least one publication reports experimental evidence evaluating an impact on protein function and this variant affected TULP1 protein function (Lobo_2016). The following publications have been ascertained in the context of this evaluation (PMID: 9462750, 31429209, 26427415, 26987071). ClinVar contains an entry for this variant (Variation ID: 7359). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

not provided Pathogenic:1

Jan 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with lysine, which is basic and polar, at codon 459 of the TULP1 protein (p.Ile459Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of inherited retinal dystrophy and/or TULP1-related conditions (PMID: 9462750, 31429209). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 7359). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects TULP1 function (PMID: 26427415, 26987071). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Uncertain	25
DANN	Benign	0.97
DEOGEN2	Pathogenic	0.88	.;D;T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Pathogenic	0.55	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.3	.;M;.
PhyloP100		7.5
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-6.0	D;D;.
REVEL	Pathogenic	0.93
Sift	Benign	0.035	D;D;.
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.41	B;B;.
Vest4		0.87
MutPred		0.85		.;Gain of helix (P = 6e-04);.;
MVP		0.99
MPC		1.2
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.73
gMVP		0.81
Mutation Taster		=10/90	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs121909075; hg19: chr6-35467877; COSMIC: COSV106333738; COSMIC: COSV106333738;