8-22163096-T-C

Position:

• chr8-22163096-T-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PS1_Moderate PM1 PM2 PP5_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 same amino acid change has been previously reported as Likely pathogenicin UniProt.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: SFTPC NM_001317778.2 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:14
• Conservation: PhyloP100: 2.22

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]

ACMG classification

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 hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain 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/exons	MANE	UniProt
SFTPC	NM_001317778.2	c.218T>C	p.Ile73Thr	missense_variant	3/6	ENST00000679463.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SFTPC	ENST00000679463.1	c.218T>C	p.Ile73Thr	missense_variant	3/6		NM_001317778.2	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461844 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727230

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.: 33

Bravo AF: 0.00000756

ExAC AF: 0.00000826 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Surfactant metabolism dysfunction, pulmonary, 2 Pathogenic:9

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 13, 2020	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2009	- -
Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Nov 26, 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. We consider this variant to be pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013208, PS1_S). Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 21092132, PS3_M). The variant was observed to be de novo (3billion dataset, PS2_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.731, PP3_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000000, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	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 -
Pathogenic, criteria provided, single submitter	clinical testing	Beijing Key Laboratry for Genetics of Birth Defects, Beijing Children's Hospital	Dec 20, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota	Aug 28, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 27, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Medicine Lab, University of California San Francisco	Oct 30, 2023	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 17, 2024	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 04, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 03, 2023	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

Likely risk allele, no assertion criteria provided

research

Garcia Pulmonary Genetics Research Laboratory, Columbia University Irving Medical Center

Jun 09, 2022

- -

Hereditary pulmonary alveolar proteinosis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 26, 2022

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	D
BayesDel_noAF	Pathogenic	0.18
CADD	Uncertain	25
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	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;D;D
M_CAP	Pathogenic	0.82	D
MetaRNN	Uncertain	0.66	D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.91	D
MutationTaster	Benign	0.88	A;A;A;A;A;A
PrimateAI	Uncertain	0.56	T
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	D
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

Other links and lift over

dbSNP: rs121917834; hg19: chr8-22020609;