chr8-22163096-T-C

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PS1_ModeratePM1PM2PP5_Very_Strong

The NM_001317778.2(SFTPC):c.218T>C(p.Ile73Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,844 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in UniProt.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

SFTPC
NM_001317778.2 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:14

Conservation

PhyloP100: 2.22

Variant links:

Genes affected

SFTPC (HGNC:10802): (surfactant protein C) This gene encodes the pulmonary-associated surfactant protein C (SPC), an extremely hydrophobic surfactant protein essential for lung function and homeostasis after birth. Pulmonary surfactant is a surface-active lipoprotein complex composed of 90% lipids and 10% proteins which include plasma proteins and apolipoproteins SPA, SPB, SPC and SPD. The surfactant is secreted by the alveolar cells of the lung and maintains the stability of pulmonary tissue by reducing the surface tension of fluids that coat the lung. Multiple mutations in this gene have been identified, which cause pulmonary surfactant metabolism dysfunction type 2, also called pulmonary alveolar proteinosis due to surfactant protein C deficiency, and are associated with interstitial lung disease in older infants, children, and adults. Alternatively spliced transcript variants encoding different protein isoforms have been identified.[provided by RefSeq, Feb 2010]

SFTPC links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PS1

Transcript NM_001317778.2 (SFTPC) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt

PM1

In a propeptide (size 138) in uniprot entity PSPC_HUMAN there are 19 pathogenic changes around while only 2 benign (90%) in NM_001317778.2

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 8-22163096-T-C is Pathogenic according to our data. Variant chr8-22163096-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 13208.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-22163096-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SFTPC	NM_001317778.2 link	c.218T>C	p.Ile73Thr	missense_variant	Exon 3 of 6	ENST00000679463.1	NP_001304707.1	P11686A0A0A0MTC9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SFTPC	ENST00000679463.1 link	c.218T>C	p.Ile73Thr	missense_variant	Exon 3 of 6		NM_001317778.2	ENSP00000505152.1		A0A0A0MTC9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461844

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727230

show subpopulations

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:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000826

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Surfactant metabolism dysfunction, pulmonary, 2

Pathogenic:9

Oct 30, 2023

Genomic Medicine Lab, University of California San Francisco

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 20, 2023

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.007%). Predicted Consequence/Location: The majority of the known disease-causing variants of this gene are variants expected to result in premature termination of the protein. In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.87 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.85 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000497221 /PMID: 15870973). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -

Jul 01, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Nov 26, 2019

Johns Hopkins Genomics, Johns Hopkins University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This previously reported SFTPC variant results in mistrafficking of the SFTPC pre-protein and has been identified in multiple individuals with surfactant protein C deficiency. We consider this variant to be pathogenic. -

Feb 27, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 13, 2020

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Ile73Thr variant has been previously reported in patients affected with interstitial lung disease (Liu et al, 2019). This previously reported SFTPC variant results in mistrafficking of the SFTPC pre-protein and has been identified in multiple individuals with surfactant protein C deficiency. This variant has been reported to the ClinVar database as Pathogenic. This variant is novel (not in any individuals) in 1000 Genomes. The amino acid Ile at position 73 is changed to a Thr changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid change p.Ile73Thr in SFTPC is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic -

Aug 28, 2017

Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 20, 2020

Beijing Key Laboratry for Genetics of Birth Defects, Beijing Children's Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:3

Jan 04, 2018

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 17, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate damaging effects including impaired uptake and degradation of surfactant phospholipid and accumulation of dysfunctional mitochondria (PMID: 21707890, 25344067); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22461427, 26925580, 15572558, 32851322, 21707890, 25582472, 11893657, 25344067, 18643778, 21092132, 25553246, 20371530, 23701443, 15756222, 23926107, 25755194, 17597647, 15293602, 29569581, 31081264, 30630227, 31462320, 32095252, 28495692, 34134972, 33942430) -

Aug 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 73 of the SFTPC protein (p.Ile73Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with childhood interstitial lung disease (PMID: 15293602, 15572558, 15756222). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13208). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects SFTPC function (PMID: 21707890). For these reasons, this variant has been classified as Pathogenic. -

Pulmonary fibrosis

Pathogenic:1

Jun 09, 2022

Garcia Pulmonary Genetics Research Laboratory, Columbia University Irving Medical Center

Significance: Likely risk allele

Review Status: no assertion criteria provided

Collection Method: research

- -

Hereditary pulmonary alveolar proteinosis

Pathogenic:1

Aug 26, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.218T>C (p.I73T) alteration is located in exon 3 (coding exon 3) of the SFTPC gene. This alteration results from a T to C substitution at nucleotide position 218, causing the isoleucine (I) at amino acid position 73 to be replaced by a threonine (T). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This mutation is considered to account for approximately 30% of described mutations in the SFTPC gene. It was described in a large kindred with multiple individuals to co-segregate with lung disease of variable severity (Cameron, 2005) and has been reported as a de novo occurrence in several unrelated patients (Guillot, 2009). This amino acid position is not well conserved in available vertebrate species. In vitro studies have demonstrated that this alteration interferes with correct processing and routing of the final protein, as well as reduction in lipid degradation (Beers, 2011). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.18

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.043

T;T;.;D;D;T;D

Eigen

Uncertain

0.22

Eigen_PC

Benign

0.22

FATHMM_MKL

Benign

0.61

LIST_S2

Uncertain

0.90

D;D;D;D;D;D;D

M_CAP

Pathogenic

0.82

MetaRNN

Uncertain

0.66

D;D;D;D;D;D;D

MetaSVM

Pathogenic

0.91

PrimateAI

Uncertain

0.56

PROVEAN

Uncertain

-2.6

D;N;D;D;D;D;D

REVEL

Pathogenic

0.73

Sift

Uncertain

0.0030

D;D;D;D;D;D;D

Sift4G

Uncertain

0.0060

D;D;D;D;D;D;D

Polyphen

0.84, 0.55

.;.;P;.;P;.;.

Vest4

0.59

MVP

1.0

MPC

1.2

ClinPred

0.82

GERP RS

4.7

gMVP

0.83

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over