10-122506767-C-T

Position:

• chr10-122506767-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_002775.5(HTRA1):​c.854C>T​(p.Pro285Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,656 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/21 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. P285Q) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: HTRA1 NM_002775.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 U:1 O:1
• Conservation: PhyloP100: 7.75

Genes affected

HTRA1 (HGNC:9476): (HtrA serine peptidase 1) This gene encodes a member of the trypsin family of serine proteases. This protein is a secreted enzyme that is proposed to regulate the availability of insulin-like growth factors (IGFs) by cleaving IGF-binding proteins. It has also been suggested to be a regulator of cell growth. Variations in the promoter region of this gene are the cause of susceptibility to age-related macular degeneration type 7. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a region_of_interest Serine protease (size 160) in uniprot entity HTRA1_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_002775.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985
• PP5: Variant 10-122506767-C-T is Pathogenic according to our data. Variant chr10-122506767-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 156100.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HTRA1	NM_002775.5	c.854C>T	p.Pro285Leu	missense_variant	4/9	ENST00000368984.8	NP_002766.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HTRA1	ENST00000368984.8	c.854C>T	p.Pro285Leu	missense_variant	4/9	1	NM_002775.5	ENSP00000357980.3
HTRA1	ENST00000648167.1	c.536C>T	p.Pro179Leu	missense_variant	4/9			ENSP00000498033.1
HTRA1	ENST00000420892.1	c.77C>T	p.Pro26Leu	missense_variant	1/6	2		ENSP00000412676.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251248 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135816

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461656 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727134

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3 Uncertain:1 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 30, 2022	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. This variant disrupts the p.Pro285 amino acid residue in HTRA1. Other variant(s) that disrupt this residue have been observed in individuals with HTRA1-related conditions (PMID: 26063658), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this missense change affects HTRA1 function (PMID: 27164673). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). ClinVar contains an entry for this variant (Variation ID: 156100). This missense change has been observed in individuals with clinical features of HTRA1-related conditions (PMID: 23963851, 27164673, 27353043; Invitae). This variant is present in population databases (rs587776446, gnomAD 0.006%). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 285 of the HTRA1 protein (p.Pro285Leu). -

CARASIL syndrome Uncertain:1 Other:1

Uncertain significance, flagged submission	clinical testing	Center of Genomic medicine, Geneva, University Hospital of Geneva	Sep 18, 2015	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

HTRA1-related cerebral small vessel disease Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Oct 25, 2023

Variant summary: HTRA1 c.854C>T (p.Pro285Leu) 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 allele was found at a frequency of 4e-06 in 251248 control chromosomes (gnomAD). c.854C>T has been reported in the literature in the homozygous state in an individual affected with HTRA1-Related Cerebral Small Vessel Disease, with a brother who was similarly affected but was not available for genetic testing, and whose parents were heterozygous for the variant, the father reportedly having moderate symptoms (Chen_2013). The variant has also been reported in the heterozygous state in multiple individuals with a clinical diagnosis and/or features of HTRA1-Related Cerebral Small Vessel Disease, primarily with an adult onset of over 45 years of age (e.g. Nozaki_2016, Fokstuen_2016, Zhang_2022, Uemura_2023, He_2023). In one report the variant was found in several family members, including two siblings who both both presented with more severe symptoms such as gait disturbances, with white matter hyperintensities and lacunar infarcts at the ages of 59 and 64, whereas of the three younger relatives with the variant, one had alopecia and memory loss at age 30 and the other two (aged 28 and 14) did not manifest symptoms (He_2023). Altogether, these data indicate that the variant is very likely to be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function (e.g. Nozaki_2016, Zhang_2022). The most pronounced variant effect results in 10%-<30% protease activity compared to the wild type protein. The following publications have been ascertained in the context of this evaluation (PMID: 23963851, 27353043, 36253578, 27164673, 36261288, 36047879, 36380532). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Two submitters classified the variant as pathogenic/likely pathogenic and one classified it as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.92	.;D;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.1	.;H;.
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-9.6	.;D;D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.016	.;D;D
Sift4G	Uncertain	0.018	.;D;D
Polyphen		1.0	.;D;.
Vest4		0.99
MutPred		0.90		.;Gain of loop (P = 0.1069);.;
MVP		0.99
MPC		1.5
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.99
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs587776446; hg19: chr10-124266283;