NM_003322.6:c.1471T>C

Variant names:

• chr6-35500005-A-G
• rs121909074
• NM_003322.6:c.1471T>C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_003322.6(TULP1):​c.1471T>C​(p.Phe491Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,844 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging 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. F491S) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TULP1 NM_003322.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 9.32

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]

LOC124901309 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-35500004-A-G is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.96
• PP5: Variant 6-35500005-A-G is Pathogenic according to our data. Variant chr6-35500005-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 7358.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-35500005-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TULP1	NM_003322.6	c.1471T>C	p.Phe491Leu	missense_variant	Exon 14 of 15	ENST00000229771.11	NP_003313.3
TULP1	NM_001289395.2	c.1312T>C	p.Phe438Leu	missense_variant	Exon 13 of 14		NP_001276324.1
LOC124901309	XR_007059561.1	n.75+1798A>G		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TULP1	ENST00000229771.11	c.1471T>C	p.Phe491Leu	missense_variant	Exon 14 of 15	1	NM_003322.6	ENSP00000229771.6
TULP1	ENST00000322263.8	c.1312T>C	p.Phe438Leu	missense_variant	Exon 13 of 14	1		ENSP00000319414.4
TULP1	ENST00000614066.4	c.1465T>C	p.Phe489Leu	missense_variant	Exon 13 of 14	5		ENSP00000477534.1
TULP1	ENST00000495781.1	n.*65T>C		downstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461844 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727228

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000514 Hom.: 0

Bravo AF: 0.00000378

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Oct 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 491 of the TULP1 protein (p.Phe491Leu). This variant is present in population databases (rs121909074, gnomAD 0.0009%). This missense change has been observed in individual(s) with clinical features of TULP1-related conditions (PMID: 9462750, 32531858). 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. ClinVar contains an entry for this variant (Variation ID: 7358). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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). For these reasons, this variant has been classified as Pathogenic. -

Mar 14, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed multiple times with a second TULP1 variant in unrelated patients with retinal dystrophy referred for genetic testing at GeneDx and reported in the published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes in some cases (PMID: 9462750, 32531858, 36769033); Published functional studies demonstrate that F491L disrupts TULP1 transportation from the ER leading to retinal cell death (PMID: 26987071); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26427415, 33907372, 9462750, 32531858, 31964843, 36769033, 26987071) -

Dec 01, 2017

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinitis pigmentosa 14 Pathogenic:2

Feb 01, 1998

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Feb 01, 2023

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Leber congenital amaurosis Pathogenic:1

Sep 18, 2024

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.1471T>C (p.Phe491Leu) 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 was absent in 251428 control chromosomes. c.1471T>C has been reported in the literature in the compound heterozygous or presumed compound heterozygous state in multiple individuals affected with clinical features of Leber Congenital Amaurosis or inherited retinal dystrophy (example, Hagstrom_1998, Weisschuh_2020). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in severe protein mislocation, induction of the unfolded protein response, and increased apoptotic rate in vitro and in mouse retinal cells (example, Lobo_2016). The following publications have been ascertained in the context of this evaluation (PMID: 9462750, 26987071, 32531858). ClinVar contains an entry for this variant (Variation ID: 7358). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Retinal dystrophy Pathogenic:1

May 28, 2019

Blueprint 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	0.49	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	.;D;T
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.0	.;H;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-5.6	D;D;.
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0070	D;D;.
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.96
MutPred		0.98		.;Gain of sheet (P = 0.0827);.;
MVP		0.95
MPC		1.0
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.96
gMVP		0.75

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: rs121909074; hg19: chr6-35467782;